Oral suspensions and powder formulations for reconstitution comprising a menin inhibitor

Abstract

Described herein are pharmaceutical compositions comprising (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or a solvate thereof and methods of making and using such pharmaceutical compositions.

Description

WSGR Docket No. 47535-760.601ORAL SUSPENSIONS AND POWDER FORMULATIONS FOR RECONSTITUTION COMPRISING A MENIN INHIBITOR CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Number 63 / 748,345, filed January 22, 2025, which is incorporated herein by reference in its entirety .BACKGROUND

[0002] The mixed-lineage leukemia (MLL) protein is a histone methyltransferase critical for the epigenetic regulation of gene transcription. Many acute leukemias, including acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL) and mixed -lineage leukemia (MLL), are characterized by the presence of chimeric MLL fusion proteins that result from chromosomal translocations of the MLL gene located at chromosome 11, band q23 (1 lq23). Chimeric MLL fusion proteins retain approximately 1,400 amino acids of the N-terminus of MLL but are fused with one of approximately 80 partner proteins (e.g., AF4, AF9, ENL, AF10, ELL, AF6, AFlp, GAS7). MLL fusion proteins lack the original histone methyltransferase activity of the C-terminus of MLL and gain the ability to regulate transcription of numerous oncogenes, including HOX and MEIS1, resulting in increased cell proliferation and decreased cell differentiation, ultimately leading to leukemogenesis.

[0003] The menin protein, which is encoded by the Multiple Endocrine Neoplasia (MEN) gene, is a ubiquitously expressed nuclear protein that engages in interactions with DNA processing and repair proteins, chromatin modifying proteins and numerous transcription factors (Agarwal, et al.,Horm. Metab. Res., 2005, 37(6), 369-374). The association of menin with the N-terminus of MLL fusion proteins is necessary for the observed oncogenic activity of MLL fusion proteins. This association has been shown to constitutively up-regulate the expression of HOX n MEISl oncogenes and impairs proliferation and differentiation of hematopoietic cells leading to leukemia development. As menin has been shown to function as a general oncogenic cofactor in MLL-related leukemias, the interaction between menin and MLL fusion proteins and MLL represents a potential chemotherapeutic target.SUMMARY

[0004] The menin inhibitor, (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l-(2-(4-(methylsulfonyl)piperazin-l-yl)propyl)-lH-indole-2-carbonitrile (Compound 1; common name, ziftomenib) is currently under clinical investigation in adult and pediatric patients with certain forms of leukemia and in adult patients with gastrointestinal stromal tumor (GIST), and aWSGR Docket No. 47535-760.601product comprising ziftomenib, KOMZIFTI™, has been approved by the U.S. Food and Drug Administration (FDA) for treatment of adult patients with relapsed or refractory acute myeloid leukemia with a susceptible NPM1 mutation who have no satisfactory alternative treatment options. Solid formulations such as tablets and capsules are not suitable for use in pediatric patients or in older patients with comorbidities such as dysphagia or difficulty swallowing. Thus, alternatives are needed for these situations. While small amounts of liquids or soft foods can be used as suitable vehicles for such patients, alterations to a solid dosage form may affect absorption, stability, and delivery of a drug and can lead to significant changes and variability in exposure and pharmacological effect. Described herein are pharmaceutical compositions that are oral suspensions or powder formulations suitable for reconstitution as oral suspensions, and methods of making and using such pharmaceutical compositions.

[0005] In one aspect, described herein is an oral suspension comprising(S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l -(2-(4-(methylsulfonyl)piperazin-l -yl)propyl)-lH-indole-2-carbonitrile (Compound 1; common name, ziftomenib) or a solvate thereof, optionally wherein the oral suspension comprises a crystalline form of Compound 1 or a solvate thereof.

[0006] In another aspect, described herein is a powder formulation suitable for reconstitution into an oral suspension, comprising (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l-(2-(4-(methylsulfonyl)piperazin-l-yl)propyl)-lH-indole-2-carbonitrile (Compound 1; ziftomenib) or a solvate thereof. In another aspect, described herein is a powder formulation suitable for reconstitution into an oral suspension, comprising a crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l -(2-(4-(methylsulfonyl)piperazin-l -yl)propyl)-lH-indole-2-carbonitrile (Compound 1 ; ziftomenib) or a solvate thereof. In another aspect, described herein is a powder formulation suitable for reconstitution into an oral suspension, comprising (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l -(2-(4-(methylsulfonyl)piperazin-l -yl)propyl)-lH-indole-2-carbonitrile (Compound 1; ziftomenib) or a solvate thereof, optionally a crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l -(2-(4-(methylsulfonyl)piperazin-l -yl)propyl)-lH-indole-2-carbonitrile (Compound 1; ziftomenib) or a solvate thereof, and a pharmaceutically acceptable excipient.

[0007] In certain embodiments, the oral suspension is prepared from a crystalline form of Compound 1 or a solvate thereof. In certain embodiments, the powder formulation suitable for reconstitution is prepared from an oral solid dosage form of Compound 1 or a solvate thereofWSGR Docket No. 47535-760.601(e.g., a capsule or tablet oral solid dosage form). In certain embodiments, the oral suspension is prepared from a powder formulation suitable for reconstitution as described herein.

[0008] In certain embodiments of the compositions described herein, the crystalline form of Compound 1 or a solvate thereof is Form 1, having at least one of the following properties:(a) an X-ray powder diffraction (XRPD) pattern substantially similar to the one set forth in Figure 1;(b) an XRPD pattern with at least three characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2- Theta, and 22.6° 2-Theta;(c) a differential scanning calorimetry (DSC) thermogram substantially similar to the one set forth in Figure 2;(d) a DSC thermogram with an endotherm having an onset at about 136 °C and / or a peak at about 149 °C;(e) a thermogravimetric analysis (TGA) curve substantially similar to the one set forth in Figure 3; or(f) combinations thereof.

[0009] In another aspect, described herein is a method for treating a disease or condition in a subject comprising administering to the subject an oral suspension comprising a therapeutically effective amount of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l-(2-(4-(methylsulfonyl)piperazin-l-yl)propyl)-lH-indole-2-carbonitrile (Compound 1) or a solvate thereof, wherein the oral suspension comprises and / or is prepared from a crystalline form of Compound 1 or a solvate thereof (such as Form 1), and wherein the disease or condition comprises a menin-mediated disease, a hematologic malignancy, a solid tumor cancer, or diabetes.INCORPORATION BY REFERENCE

[0010] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the extent applicable and relevant and to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE FIGURES

[0011] Figure 1. Illustrates an XRPD pattern of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-WSGR Docket No. 47535-760.601yl)methyl)-l -(2-(4-(methylsulfonyl)piperazin-l -yl)propyl)-lH-indole-2-carbonitrile (Compound 1) or a solvate thereof, Form 1.

[0012] Figure 2. Illustrates a DSC thermogram of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l -(2-(4-(methylsulfonyl)piperazin-l -yl)propyl)-lH-indole-2-carbonitrile (Compound 1) or a solvate thereof, Form 1.

[0013] Figure 3. Illustrates a TGA curve of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3 -d]pyrimidin-4-yl)amino)piperidin-l -yl)methyl)-l -(2-(4-(methylsulfonyl)piperazin-l-yl)propyl)-lH-indole-2-carbonitrile (Compound 1) or a solvate thereof, Form 1.DETAILED DESCRIPTIONCertain Terminology

[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may “consist of” or “consist essentially of” the described features. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range.

[0015] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety.WSGR Docket No. 47535-760.601

[0016] The term “acceptable” or “pharmaceutically acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated or does not abrogate the biological activity or properties of the compound, and is relatively nontoxic.

[0017] As used herein, “amelioration” of the symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.

[0018] The term “bulk density” means the mass of a volume unit of solid and the term “tap density” (or “tapped density”) means the mass of a volume unit of solid after mechanically tapping a container containing the powder sample, and these can measured according to USP method <616>.

[0019] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered that will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects. An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that “an effective amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of Compound 1, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, therapeutically effective amounts may be determined by a dose escalation clinical trial. Dosing amounts provided herein for Compound 1 or a solvate thereof refer to the free base equivalent amount based on the mass of Compound 1 free base.

[0020] The term “particle size distribution” refers to the percentage of particles of a certain size (or in a certain size range) and can be measured according to USP <786> or by a light diffraction measurement per USP <429>.WSGR Docket No. 47535-760.601

[0021] The term “prophy tactically effective amount,” as used herein, refers to that amount of a composition applied to a patient which will relieve to some extent one or more of the symptoms of a disease, condition or disorder being treated. In such prophylactic applications, such amounts may depend on the patient’s state of health, weight, and the like. As an example, one can determine such prophylactically effective amounts by a dose escalation clinical trial.

[0022] The term “subject” as used herein, refers to an animal which is the object of treatment, observation or experiment. By way of example only, a subject may be, but is not limited to, a mammal including, but not limited to, a human.

[0023] The terms “treat,” “treating,” or “treatment,” as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. The terms “treat,” “treating,” or “treatment,” include, but are not limited to, prophylactic and / or therapeutic treatments.

[0024] The term “unit dosage” refers to the amount of a drug in a single dose that is to be administered to a patient.Compound 1

[0025] In one embodiment is (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l-(2-(4-(methylsulfonyl)piperazin-l-yl)propyl)-lH-indole-2-carbonitrile (Compound 1; ziftomenib) or a solvate thereof . “Compound 1” or“(S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l-(2-(4-(methylsulfonyl)piperazin-l-yl)propyl)-lH-indole-2-carbonitrile” or “ziftomenib” each refer to the free base compound with the following structure:Compound 1 is a menin inhibitor and inhibits the menin-MLL interaction. The common name of Compound 1 is ziftomenib.WSGR Docket No. 47535-760.601

[0026] In some embodiments, Compound 1 or a solvate thereof is prepared as outlined in the Examples. It is noted that solvents, temperatures, and other reaction conditions presented herein may vary.

[0027] In another embodiment, Compound 1 or a solvate thereof is substantially pure. In certain embodiments, the purity of Compound 1 or a solvate thereof is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

[0028] In some embodiments, described herein are crystalline forms of Compound 1 or solvates thereof. Solvates contain either stoichiometric or non -stoichiometric amounts of a solvent, and are formed during the process of product formation or isolation with pharmaceutically acceptable solvents such as water, ethanol (EtOH), methanol (MeOH), tertbutyl methyl ether (MTBE), diisopropyl ether, ethyl acetate (EtOAc), isopropyl acetate, isopropyl alcohol (IP A), methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile (ACN), and the like. In some embodiments, solvates are formed using, but not limited to, Class 3 solvent(s). In some embodiments, solvates are formed using, but not limited to, Class 2 solvent(s). Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents Q3C(R6),” (October 2016). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol, such as EtOH or IPA.

[0029] In other embodiments, Compound 1 or a solvate thereof is prepared in various forms, including but not limited to, an amorphous phase, crystalline forms, milled forms, and nanoparticulate forms. In other embodiments, Compound 1 or a solvate thereof is in a granule form.

[0030] While not intending to be bound by any particular theory, certain solid forms are characterized by physical properties, e.g., stability, solubility, and dissolution rate, appropriate for pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, stickiness, solubility, water uptake, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) affecting particular processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) which make certain solid forms suitable for the manufacture of a solid dosage form and / or which make certain solid forms suitable for the manufacture of oral suspensions or of solid forms for reconstitution . Such properties can be determined using particular analytical chemical techniques, including solid-state analyticalWSGR Docket No. 47535-760.601techniques (e.g., X-ray diffraction, microscopy, spectroscopy and thermal analysis), as described herein.Crystalline Forms

[0031] The identification and selection of a solid form of a pharmaceutical compound are complex, given that a change in solid form may affect a variety of physical and chemical properties, which may provide benefits or drawbacks in processing (e.g., flowability, bulk density), formulation, stability, bioavailability, storage, and handling (e.g., shipping), among other important pharmaceutical characteristics. Useful pharmaceutical solids include crystalline solids and amorphous solids, depending on the product and its mode of administration.Amorphous solids are characterized by a lack of long-range structural order, whereas crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends upon the specific application; amorphous solids are sometimes selected on the basis of, e.g., an improved dissolution profile, while crystalline solids may be desirable for properties such as, e.g., physical or chemical stability.

[0032] Whether crystalline or amorphous, solid forms of a pharmaceutical compound include single-component and multiple-component solids. Single-component solids consist essentially of the pharmaceutical compound or active ingredient in the absence of other compounds. Variety among single-component crystalline materials may potentially arise from the phenomenon of polymorphism, wherein multiple three-dimensional arrangements exist for a particular pharmaceutical compound.

[0033] Notably, it is not possible to predict a priori if crystalline forms of a compound even exist, let alone the physicochemical and biological properties of such materials, or how to successfully prepare them (see, e.g., Braga and Grepioni, Chem. Commun. 2005, 29, 3635-3645 (“with respect to crystal engineering, if instructions are not very precise and / or if other external factors affect the process, the result can be unpredictable”); Jones et al., MRS Bull. 2006, 31, 875-879 (“At present it is not generally possible to computationally predict the number of observable polymorphs of even the simplest molecules”); Price, Adv. Drug Deliv. Rev. 2004, 56(3), 301-319; and Bernstein, ACA Transactions 2004, 39, 14-23 (“a great deal still needs to be learned and done before one can state with any degree of confidence the ability to predict a crystal structure, much less polymorphic forms”)).

[0034] The variety of possible solid forms creates potential diversity in physical and chemical properties for a given pharmaceutical compound. The discovery and selection of solid forms are of great importance in the development of an effective, stable, and marketable pharmaceutical product.WSGR Docket No. 47535-760.601Crystalline Compound 1, Form 1

[0035] In some embodiments, the crystalline form of Compound 1 or a solvate thereof is Form 1, characterized as having at least one of the following properties:(a) an XRPD pattern substantially similar to the one set forth in Figure 1;(b) an XRPD pattern with at least three characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2- Theta, and 22.6° 2-Theta;(c) a differential scanning calorimetry (DSC) thermogram substantially similar to the one set forth in Figure 2;(d) a DSC thermogram with an endotherm having an onset at about 136 °C and / or a peak at about 149 °C;(e) a TGA curve substantially similar to the one set forth in Figure 3; or(f) combinations thereof.

[0036] In some embodiments, crystalline Compound 1, Form 1, is characterized as having at least two of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1 , Form 1 , is characterized as having at least three of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1, Form 1, is characterized as having at least four of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1, Form 1, is characterized as having properties (a) to (e).

[0037] In some embodiments, crystalline Compound 1, Form 1, has an XRPD pattern substantially similar to the one set forth in Figure 1. In some embodiments, crystalline Compound 1 , Form 1 , has an XRPD pattern with at least four characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta. In some embodiments, crystalline Compound 1, Form 1, has an XRPD pattern with at least five characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta. In some embodiments, crystalline Compound 1, Form 1, has an XRPD pattern with at least six characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta. In some embodiments, crystalline Compound 1, Form 1, has an XRPD pattern with at least seven characteristic peaks selected from 4.1° 2-WSGR Docket No. 47535-760.601Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2 -Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta. In some embodiments, crystalline Compound 1, Form 1, has an XRPD pattern with at least eight, or at least nine, or at least 10, or at least 11 , or at least 12, characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta. In some embodiments, crystalline Compound 1, Form 1, has an XRPD pattern with characteristic peaks at 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta. In some embodiments, crystalline Compound 1 , Form 1 , has an XRPD pattern with characteristic peaks at 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.5° 2-Theta, and 22.6° 2-Theta. In some embodiments, crystalline Compound 1, Form 1, has a DSC thermogram substantially similar to the one set forth in Figure 2. In some embodiments, crystalline Compound l, Form 1, has a DSC thermogram with an endotherm having an onset at about 136 °C. In some embodiments, crystalline Compound 1, Form 1, has a DSC thermogram with an endotherm having a peak at about 149 °C. In some embodiments, crystalline Compound 1, Form 1, has a TGA curve substantially similar to the one set forth in Figure 3. In some embodiments, crystalline Compound 1, Form 1, has a TGA curve that exhibits a weight loss of about0.60% overthe range of about29 °C to about 150 °C. In some embodiments, crystalline Compound 1, Form 1, is an anhydrate. In some embodiments, crystalline Compound 1, Form 1, is obtained from MEK and IPA. In some embodiments crystalline Compound 1, Form 1, is obtained from a 1 : 1 mixture of MEK and IPA. In some embodiments, crystalline Compound 1, Form 1, is obtained from toluene. In some embodiments, crystalline Compound 1, Form 1, is obtained from MTBE.

[0038] Additional crystalline forms of Compound 1 or a solvate thereof include Form 2, Form 3, Form 4, and Form 5, which are described in more detail in the Examples section.Preparation of Crystalline Compound 1

[0039] In some embodiments, crystalline forms of Compound 1 or a solvate thereof are prepared as outlined in the Examples. It is noted that solvents, temperatures and other reaction conditions presented herein may vary.

[0040] In another embodiment, crystalline Compound 1, Form 1, is substantially pure. In certain embodiments, the substantially pure crystalline Compound 1, Form 1, is substantially free of other solid forms, e.g., amorphous solid. In certain embodiments, the purity of theWSGR Docket No. 47535-760.601substantially pure crystalline Compound 1 , Form 1 , is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

[0041] In some embodiments, crystalline Compound 1, Form 1, is obtained from MEK and IPA with wet milling during the crystallization process. In some embodiments, Compound 1, Form 1, has a bulk density of at least 0.1 g / cm3, or from about 0.1 to about 0.2 g / cm3, or from aboutO.l to about 0.15 g / cm3, oraboutO.il, 0.12, 0.13,0.14, or0.15g / cm3, orabout0.16, 0.17, 0.18, 0.19, orO.20 g / cm3. In some aspects, the crystalline Compound 1, Form 1, has a particle size distribution (as measured by a light diffraction method developed per USP <429>) of : Di0, 1.5 to 4.5 pm, or about2.0 to about4.0 pm, or about3.8 to about 3.9 pm, or about 2.9 to about 3.7 pm; D50, 5 to 11 pm, or about 5 to about 8 pm, or about 5.8 to about 7.7 pm, or about or about 9.5 to about 10.5 pm; orD90, 13 to 50 pm, or about 33 to about 45 pm, or about 13 to about 26 pm, or about 13 to about 18 pm. In some aspects, the particle size distribution D90equal to or below 50 pm.

[0042] In some embodiments, a crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l-(2-(4-(methylsulfonyl)piperazin-l-yl)propyl)-lH-indole-2-carbonitrile is prepared by heating (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l-(2-(4-(methylsulfonyl)piperazin-l-yl)propyl)-lH-indole-2-carbonitrile in a mixture of MEK and IPA to a first temperature of about 35 to 45 °C (optionally wherein the first temperature is about 40 °C) to form a diluted suspension, optionally maintaining the diluted suspension at the first temperature for 3 to 48 h, wet milling the diluted suspension at the first temperature, optionally performing a second wet milling on the diluted suspension at about 25 °C, and filtering the diluted suspension to provide the crystalline form. In some embodiments, the method comprises dissolving (S)-4-methyl-5 -((4-((2-(m ethylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3 -d]pyrimidin-4-yl)amino)piperidin-l -yl)methyl)-l -(2-(4-(methylsulfonyl)piperazin-l-yl)propyl)-lH-indole-2-carbonitrile in the MEK to form a solution, heatingthe solution to the first temperature, and adding the IPA to form the diluted suspension, optionally wherein the MEK / IPA v / v ratio is from about 2:3 to about 1:10, or from about 1 :2 to about 1 :8, or is about 1 :2, 2:5, or 1 :7, or is about 1 :7, or is about 2:5.Suitable Solvents

[0043] Therapeutic agents that are administrable to mammals, such as humans, must be prepared by following regulatory guidelines. Such government regulated guidelines are referred to as Good Manufacturing Practice (GMP). GMP guidelines outline acceptable contaminationWSGR Docket No. 47535-760.601levels of active therapeutic agents, such as, for example, the amount of residual solvent in the final product. In some embodiments, solvents disclosed herein are those that are suitable for use in GMP facilities and consistent with industrial safety concerns. Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities:Guidelines for Residual Solvents Q3C(R6),” (October 2016).

[0044] Solvents are categorized into three classes. Class 1 solvents are toxic and are to be avoided. Class 2 solvents are solvents to be limited in use during the manufacture of the therapeutic agent. Class 3 solvents are solvents with low toxic potential and of lower risk to human health. Data for Class 3 solvents indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies.

[0045] Class 1 solvents, which are to be avoided, include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1 -dichloroethene; and 1,1,1 -trichloroethane.

[0046] Examples of Class 2 solvents are: ACN, chlorobenzene, chloroform, cumene, cyclohexane, 1 ,2-dichloroethene, DCM, l,2-dimethoxyethane,N,N-dim ethylacetamide (DMA), N,N-dimethylformamide, 1,4-dioxane, 2-ethoxy ethanol, ethylene glycol, formamide, hexane, MeOH, 2 -methoxy ethanol, methylbutyl ketone, methylcyclohexane, MIBK, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, THF, tetralin, toluene, 1,1,2-trichloroethene and xylene.

[0047] Class 3 solvents, which possess low toxicity, include: acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, MTBE, dimethylsulfoxide (DMSO), EtOH, EtOAc, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl- 1 -butanol, MEK, 2 -methyl- 1 -propanol, pentane, 1 -pentanol, 1 -propanol, IP A, propyl acetate, and triethylamine.

[0048] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacture of APIs. In some cases, the solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of APIs may improve the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent is a critical parameter in the synthetic process.

[0049] In some embodiments, compositions comprising Compound 1 or a solvate thereof, or a crystalline form of Compound 1 or a solvate thereof, comprise an organic solvent(s). In some embodiments, compositions comprising Compound 1 or a solvate thereof, or a crystalline form of Compound 1 or a solvate thereof, comprise a residual amount of an organic solvent(s). In some embodiments, compositions comprising Compound 1 or a solvate thereof, or a crystalline form of Compound 1 or a solvate thereof, comprise a residual amount of a Class 3 solvent. InWSGR Docket No. 47535-760.601some embodiments, the organic solvent is a Class 3 solvent, for example a Class 3 solvent listed above. In some embodiments, the Class 3 solvent is selected from the group consisting of acetone, EtOAc, isopropyl acetate, MTBE, heptane, IP A, and EtOH. In some embodiments, the organic solvent is a Class 2 solvent, for example a Class 2 solvent listed above. In some embodiments, the Class 2 solvent is ACN, THF, or toluene. In some embodiments, the Class 2 solvent is ACN. In some embodiments, the organic solvent is 2-butanone or 2-methyltetrahydrofuran (2 -Me THF).Oral Suspensions / Powders for Reconstitution

[0050] In one aspect, described herein is an oral suspension comprising(S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l -(2-(4-(methylsulfonyl)piperazin-l -yl)propyl)-lH-indole-2-carbonitrile (Compound 1) or a solvate thereof. In some embodiments, the oral suspension comprises a crystalline form of Compound 1 or a solvate thereof. In some embodiments, the oral suspension is prepared with a crystalline form of Compound 1 or a solvate thereof. In some embodiments, the oral suspension comprises Compound 1, Form 1. In some embodiments, the oral suspension is prepared with Compound 1, Form 1. In some embodiments, the oral suspension is prepared from a powder formulation suitable for reconstitution, wherein the powder formulation comprises Compound 1 or a solvate thereof, a crystalline form of Compound 1 or a solvate thereof, or Compound 1, Form 1. In some embodiments, the powder formulation comprises a pharmaceutically acceptable excipient. In some embodiments, the powder formulation comprises only Compound 1 or a solvate thereof, or a crystalline form of Compound 1 or a solvate thereof, or Compound 1, Form 1, and no additives.

[0051] In some embodiments, an oral suspension comprises 5 to 75 mg / mL, or 10 to 75 mg / mL, or 10 to 30 mg / mL, or 40 to 60 mg / mL, or 10, 20, 25, 30, 40, or 50 mg / mL, or 20 mg / mL, or 50 mg / mL of Compound 1 or a solvate thereof, or of a crystalline form of Compound 1 or a solvate thereof, or of Compound 1, Form 1.

[0052] In some embodiments, an oral suspension, such as a unit dosage of an oral suspension, comprises 25 to 1200 mg of Compound 1 or a solvate thereof, or 25 to 800 mg of Compound 1 or a solvate thereof, or 50, 75, 100, 125, 150,200,250,300,350,400,450, 500, 550, 600, 650, 700, 750, or 800 mg of Compound 1 or a solvate thereof. In some embodiments, an oral suspension, such as a unit dosage of an oral suspension, comprises 25 to 1200 mg of a crystalline form of Compound 1 or a solvate thereof, or 25 to 800 mg of a crystalline form of Compound 1 ora solvate thereof, or 50, 75, 100, 125, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, or 800 mg of a crystalline form of Compound 1 or a solvate thereof. InWSGR Docket No. 47535-760.601some embodiments, an oral suspension, such as a unit dosage of an oral suspension, comprises 25 to 1200 mg of Compound 1, Form 1, or 25 to 800 mg of Compound 1, Form 1, or 50, 75, 100, 125, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, or 800 mg of Compound 1, Form 1.

[0053] In some embodiments, an oral suspension, such as a unit dosage of an oral suspension, comprises 65, 75, 90, 100, 115, 125, 140, 150, 165, 175, 190,200,225,250,300,325,350,375, 400, 450, 475, 500, 550, 575, 600, 625, 675, 725, 775, or 800 mg of Compound 1 or a solvate thereof. In some embodiments, an oral suspension, such as a unit dosage of an oral suspension, comprises 65, 75, 90, 100, 115, 125, 140, 150, 165, 175, 190,200,225,250,300,325,350,375, 400, 450, 475, 500, 550, 575, 600, 625, 675, 725, 775, or 800 mg of a crystalline form of Compound 1 or a solvate thereof. In some embodiments, an oral suspension, such as a unit dosage of an oral suspension, comprises 65, 75, 90, 100, 115, 125, 140, 150, 165, 175, 190,200, 225, 250, 300, 325, 350, 375, 400, 450, 475, 500, 550, 575, 600, 625, 675, 725, 775, or 800 mg of Compound 1, Form 1. In some embodiments, a unit dosage is 100 to 500mg / m2, or 115, 235, 350, or 470 mg / m2, based on body surface area (BSA; Mosteller formula). In some such embodiments, the subject to be treated with such unit dosage amounts is > 1 year of age and < 21 years of age, or has a body weight of > 10 kg.

[0054] In some embodiments, an oral suspension, such as a unit dosage of an oral suspension, comprises 25 to 100 mg, or 25, 50, 70, or 100 mg of Compound 1 or a solvate thereof, or of a crystalline form of Compound 1 or a solvate thereof, or of Compound 1, Form 1 . In some embodiments, aunit dosage comprises 5 to 12 mg / kg, or 5.6 mg / kg, 8.3 mg / kg, or 11.1 mg / kg, based on the subject’ s body weight in kg. In some such embodiments, the subject to be treated with such unit dosage amounts is < 1 year of age or has a body weight of < 10 kg.

[0055] In some embodiments, the oral suspension comprises a suspension carrier. In some embodiments, the suspension carrier is a liquid vehicle or a soft food vehicle. In some embodiments, the suspension carrier is a liquid vehicle. In some embodiments, the liquid vehicle is selected from water, saline solution, electrolyte solution (e.g., Pedialyte), milk, coconut milk, soybean milk, buttermilk, fruit juice (e.g., orange, apple, cranberry, grapefruit, or pineapple juice), honey, or syrup (e.g., maple, chocolate, or flavoring syrup (such as Ora-sweet)). In some embodiments, the liquid vehicle is water or fruit juice. In some embodiments, the liquid vehicle is water. In some embodiments, the suspension carrier is a soft food vehicle. In some embodiments, the soft food vehicle is pureed fruit (e.g., apples, bananas, strawberries), applesauce (e.g., no sugar added applesauce), jellies or jams (e.g., fruit jelly, fruit jam, fruit marmalade), yogurt, pudding (e.g., chocolate, rice), ice cream shake (e.g., vanilla or chocolate shake), pureed vegetables (e.g., carrots), or a nut or seed butter (e.g., peanut butter, sunflowerWSGR Docket No. 47535-760.601seed butter, almond butter). In some embodiments, the suspension carrier is water, 0.9% saline, milk, or orange juice. In some embodiments, the suspension carrier is water.

[0056] In some embodiments, the oral suspension is administered by mouth (e.g., by the patient drinking or eating the suspension depending on the suspension carrier), by syringe (e.g., by dispensingthe oral suspension from a syringe into the patient’s mouth), or by an enteral feeding tube (e.g., nasogastric tube, orogastric tube, gastric tube, nasoenteric tube, or oroenteric tube).

[0057] In another aspect, described herein is a powder formulation suitable for reconstitution as an oral suspension, wherein the powder formulation comprises Compound 1 or a solvate thereof as described herein. In another aspect, described herein is a powder formulation suitable for reconstitution as an oral suspension, wherein the powder formulation comprises a crystalline form of Compound 1 or a solvate thereof as described herein. In some embodiments, the powder formulation comprises Compound 1, Form 1. In some embodiments, the oral suspension is prepared with the powder formulation using conventional means, such as mixing the powder formulation with the suspension carrier, such as the liquid vehicle or the soft food vehicle. Mixing may be accomplished by stirring, swirling, shaking, or otherwise agitating the components to produce a homogeneous combination of powder and suspension carrier.

[0058] In some embodiments, a powder formulation described herein comprises 25 to 1200 mg of Compound 1 or a solvate thereof, or 25 to 800 mg of Compound 1 or a solvate thereof, or 50, 75, 100, 125, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, or 800 mg, or 25, 50, or 200 mg of Compound 1 or a solvate thereof. In some embodiments, a powder formulation described herein comprises 25 to 1200 mg of Compound 1, Form 1, or 25 to 800 mg of Compound 1, Form 1, or 50, 75, 100, 125, 150,200,250,300, 350,400, 450, 500, 550, 600, 650, 700, 750, or 800 mg, or 25, 50 or 200 mg of Compound 1, Form 1.

[0059] In some embodiments, the powder formulation, such as a unit dosage of the powder formulation, comprises 25 to 1200 mg of Compound 1 or a solvate thereof, or 25 to 800 mg of Compound 1 or a solvate thereof, or 25, 50, 75, 100, 125, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, or 800 mg of Compound 1 or a solvate thereof. In some embodiments, the powder formulation, such as a unit dosage of the powder formulation, comprises 25 to 1200 mg of a crystalline form of Compound 1 or a solvate thereof, or 25 to 800 mg of a crystalline form of Compound 1 or a solvate thereof, or 25, 50, 75, 100, 125, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, or 800 mg of a crystalline form of Compound 1 or a solvate thereof. In some embodiments, the powder formulation, such as a unit dosage of the powder formulation, comprises 25 to 1200 mg of Compound 1, Form 1, or 25 to 800 mgof Compound 1, Form 1, or 25, 50, 75, 100, 125, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, or 800 mg of Compound 1, Form 1.WSGR Docket No. 47535-760.601

[0060] In some embodiments, the powder formulation, such as a unit dosage of the powder formulation, comprises 65, 75, 90, 100, 115, 125, 140, 150, 165, 175, 190, 200, 225, 250, 300, 325, 350, 375, 400, 450, 475, 500, 550, 575, 600, 625, 675, 725, 775, or 800 mg of Compound 1 or a solvate thereof. In some embodiments, the powder formulation, such as a unit dosage of the powder formulation, comprises 65, 75, 90, 100, 115, 125, 140, 150, 165, 175, 190, 200, 225, 250, 300, 325, 350, 375, 400, 450, 475, 500, 550, 575 , 600, 625, 675, 725, 775, or 800 mg of a crystalline form of Compound 1 or a solvate thereof. In some embodiments, the powder formulation, such as a unit dosage of the powder formulation, comprises 65, 75, 90, 100, 115, 125, 140, 150, 165, 175, 190,200,225,250,300,325,350,375, 400, 450, 475, 500, 550, 575, 600, 625, 675, 725, 775, or 800 mg of Compound 1, Form 1. In some embodiments, a unit dosage is 100 to 500 mg / m2, or 115, 235, 350, or 470 mg / m2, based on body surface area (BSA; Mosteller formula). In some such embodiments, the subject to be treated with such unit dosage amounts is > 1 year of age and < 21 years of age, or has a body weight of > 10 kg.

[0061] In some embodiments, the powder formulation, such as a unit dosage of the powder formulation, comprises 25 to 100 mg, or 25, 50, 70, or 100 mg of Compound 1 or a solvate thereof, or of a crystalline form of Compound 1 or a solvate thereof, or of Compound 1 , Form 1. In some embodiments, a unit dosage comprises 5 to 12 mg / kg, or 5.6 mg / kg, 8.3 mg / kg, or 11.1 mg / kg, based on the subject’s body weight in kg. In some such embodiments, the subject to be treated with such unit dosage amounts is < 1 year of age or has a body weight of < 10 kg.

[0062] In some embodiments, a powder formulation for reconstitution described herein is prepared and stored in powder form, or is prepared from an oral solid dosage form, such as a capsule or tablet. In some embodiments, a capsule comprises a powder formulation within a capsule shell, and the capsule shell may be opened to provide the powder formulation for reconstitution. In some embodiments, the powder formulation for reconstitution is prepared by crushing a tablet.

[0063] In some embodiments, oral solid dosage forms such as capsules and tablets comprise Compound 1 or a solvate thereof as described herein, and a pharmaceutically acceptable excipient. In some embodiments, the oral solid dosage form comprises a crystalline form of Compound 1 or a solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the oral solid dosage form comprises Compound 1, Form 1, and a pharmaceutically acceptable excipient. Such solid dosage forms may be prepared in conventional ways, such as mixing, dissolving, granulating, dragee -making, levigating, emulsifying, encapsulating, entrapping or compression processes one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administrationWSGR Docket No. 47535-760.601chosen. A summary of pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy , Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington ’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety. Pharmaceutically acceptable excipients may include, for example, diluents, fillers, binders, disintegrants, glidants, lubricants, carriers, stabilizers, dispersing agents, suspending agents, surfactants, and thickening agents.

[0064] In some embodiments, any of the oral suspension, the powder formulation for reconstitution, the oral solid dosage form, the capsule, or the tablet, comprise a crystalline form of Compound 1 or a solvate thereof. In some embodiments, the crystalline form is crystalline Compound 1, Form 1. In some embodiments, Compound 1, Form 1, has a bulk density of at least 0.1 g / cm3, or from about 0.1 to about 0.2 g / cm3, or from about 0.1 to about 0.15 g / cm3, or about0.ll, 0.12, 0.13, 0.14,or0.15 g / cm3, orabout0.16, 0.17, 0.18, 0.19,or0.20 g / cm3, and / or a particle size distribution (e.g., as measured by a light diffraction method developed per USP <429>) of: Dio, L5 to 4.5 pm, or about 2.0 to about 4.0 pm, or about 3.8 to about 3.9 pm, or about 2.9 to about 3.7 pm; D50, 5 to 11 pm, or about 5 to about 8 pm, or about 5.8 to about 7.7 pm, or about or about 9.5 to about 10.5 pm; orD90, 13 to 50 pm, orabout33 to about45 pm, or about 13 to about 26 pm, or about 13 to about 18 pm. In some aspects, the particle size distribution D90equal to or below 50 pm.

[0065] In some embodiments, the powder formulation for reconstitution is obtained from an oral solid dosage form. In some embodiments, the oral solid dosage form is a capsule. In some embodiments, the oral solid dosage form is a tablet. In some embodiments, the oral solid dosage form is a capsule, and the powder formulation for reconstitution is the capsule contents or a portion thereof. In some embodiments, the powder formulation for reconstitution is a crushed tablet or a portion thereof. In some embodiments, the oral solid dosage form, such as the capsule or tablet, comprises from 15 to 800 mg, or 25 to 800 mg, or 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg, or 25, 50, 200, or 300 mg of Compound 1 or a solvate thereof, or of a crystalline form of Compound 1 or a solvate thereof, or Compound 1, Form 1. In some embodiments, the oral solid dosage form, such as the capsule or tablet, comprises from 15 to 800 mg, or 25 to 800 mg, or 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg, or 25, 50, 200, or 300 mg of Compound 1, Form 1. In some embodiments, the oral solid dosage form is a capsule or a tablet.WSGR Docket No. 47535-760.601Open Capsule Formulations

[0066] In some embodiments, a powder formulation described herein comprises Compound 1 or a solvate thereof, or a crystalline form of Compound 1 or a solvate thereof, or Compound 1, Form 1. In some embodiments, the powder formulation comprises Compound 1 or a solvate thereof, or crystalline Compound 1 or a solvate thereof, or Compound 1, Form 1, and a pharmaceutically acceptable excipient. In some embodiments, the powder formulation comprises a filler, a disintegrant, a surfactant, or a lubricant, or a combination thereof. In some embodiments, the powder formulation comprises two fillers, optionally wherein the fillers comprise mannitol and / or microcrystalline cellulose. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the pharmaceutically acceptable excipient is selected from mannitol, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate, and combinations thereof. In some embodiments, the powder formulation comprises Compound 1 or a solvate thereof, mannitol, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. In some embodiments, the powder formulation comprises a crystalline form of Compound 1 or a solvate thereof. In some embodiments, the powder formulation comprises crystalline Compound 1, Form 1. In some embodiments, the quantitative composition for a powder formulation comprises Compound 1 or a solvate thereof, or a crystalline form of Compound 1 ora solvate thereof, such as Compound 1, Form 1, and one or more the following excipients in the relative amounts listed in Table 1. In some embodiments, the powder formulation is the capsule content from a capsule solid dosage form. In some embodiments, a selected dosage of powder formulation is prepared from one or more capsules, and each capsule comprises 25 mg, 50 mg, or 200 mg of Compound 1 or a solvate thereof.Table 1.

[0067] In some embodiments, the powder formulation comprises each of these ingredients in the % w / w ranges listed. In some embodiments, the powder formulation comprises granules comprising Compound 1 or a solvate thereof, or a crystalline form of Compound 1 or a solvate thereof, or Compound 1, Form 1, one or more fillers (e.g., mannitol and / or microcrystallineWSGR Docket No. 47535-760.601cellulose (about35 to 85 % w / w, or about 45 to 85 % w / w, or about 47 % w / w, or about 58 % w / w), a disintegrant (e.g., croscarmellose sodium) (about 1 to 10% w / w, or about 3 to 10 % w / w, or about 4 to 8 % w / w, or about 6 % w / w), a surfactant (e.g., sodium lauryl sulfate) (about 0.1 to 1.0 % w / w, or about 0.2 to 0.8 % w / w, or about 0.4 to 0.6 % w / w, or about 0.5 % w / w), and a lubricant (e.g., magnesium stearate) (about 0.1 to 1.0 % w / w, or about 0.2 to 0.8 % w / w, or about 0.4 to 0.6 % w / w, or about 0.5 % w / w). In some embodiments, the powder formulation comprises granules comprising Compound 1 or a solvate thereof, or a crystalline form of Compound 1 ora solvate thereof, or Compound 1, Form 1, mannitol (about 15 to 75 % w / w, or about 25 to 35 % w / w, or about 25 to 30 % w / w, or about 28 to 32 % w / w, or about 29 % w / w), microcrystalline cellulose (about 10 to 35 % w / w, or about 25 to 35 % w / w, or about 25 to 30 % w / w, or about 28 to 32 % w / w, or about 29 % w / w), croscarmellose sodium (about 1 to 10% w / w, or about 3 to 10 % w / w, or about 4 to 8 % w / w, or about 6 % w / w), sodium lauryl sulfate (about 0.1 to 1.0 % w / w, or about 0.2 to 0.8 % w / w, or about 0.4 to 0.6 % w / w, or about 0.5 % w / w), and magnesium stearate (about 0.1 to 1.0 % w / w, or about 0.2 to 0.8 % w / w, or about 0.4 to 0.6 % w / w, or about 0.5 % w / w). In some embodiments, the powder formulation comprises the granules and additional extragranular filler (e.g., mannitol). In some embodiments, the powder formulation comprises the granules and extragranular lubricant.

[0068] In some embodiments, the powder formulation comprises one of the following three exemplary lists of ingredients in the relative amounts listed in Table 2, with the amounts adjusted proportionally needed for the desired dosage.Table 2.* Optionally, such as for a 25.0 mg strength capsule, granules comprise the listed ingredients in the amounts shown, with the exception of mannitol and / or magnesium stearate, for which a portion is included in the granules and a portion is extragranular. See, e.g., Example 5 and Table 7.

[0069] In some embodiments, the powder formulations in this section are prepared from one or more capsule solid dosage forms (as appropriate for the selected dosage) with the same compositions described here, along with a capsule shell, such as a hydroxypropylWSGR Docket No. 47535-760.601methylcellulose (HPMC) capsule shell. In some embodiments, the capsule(s) are opened to provide the powder formulation with the same composition as the capsule load and the resulting powder formulation is then suitable for reconstitution.Crushed Tablet Formulations

[0070] In some embodiments, the powder formulation comprises Compound 1 or a solvate thereof, or a crystalline form of Compound 1 or a solvate thereof, or Compound 1, Form 1 and a pharmaceutically acceptable excipient selected from a filler, a disintegrant, a surfactant, glidant, or a lubricant, or a combination thereof. In some embodiments, the powder formulation comprises a filler, optionally wherein the filler is selected from microcrystalline cellulose, lactose (e.g., lactose anhydrous), mannitol, and combinations thereof, or is microcrystalline cellulose and either lactose (e.g., lactose anhydrous) or mannitol. In some embodiments, the powder formulation comprises a disintegrant, optionally wherein the disintegrant is croscarmellose sodium or crospovidone. In some embodiments, the powder formulation comprises a binder, optionally wherein the binder is hydroxypropylcellulose. In some embodiments, the powder formulation comprises a surfactant, optionally wherein the surfactant is sodium lauryl sulfate. In some embodiments, the powder formulation comprises a glidant, optionally wherein the glidant is colloidal silicon dioxide. In some embodiments, the powder formulation comprises a lubricant, optionally wherein the lubricant is magnesium stearate. In some embodiments, the powder formulation comprises microcrystalline cellulose, lactose (e.g., lactose anhydrous), hydroxypropylcellulose, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, or magnesium stearate, or any combination thereof. In some embodiments, the powder formulation comprises microcrystalline cellulose, lactose (e.g., lactose anhydrous), hydroxypropylcellulose, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the powder formulation comprises granules and an extragranular portion.

[0071] In some embodiments, the quantitative composition for the powder formulation comprises Compound 1 or a solvate thereof, or a crystalline form of Compound 1 or a solvate thereof, such as Compound 1, Form 1, and one or more the following excipients in the % w / w ranges listed in Table 3.Table 3.WSGR Docket No. 47535-760.601

[0072] Compound 1 may be used in a % w / w range of about 35 to 75, or about 45 to 55, or about 60 to 75, or may be about 50 or about 67% w / w. Compound 1 may be used in a crystalline form. Compound 1 may be used as Form 1 or an amorphous form of the free base. Compound 1 may be used as free base Form 1 as described herein.

[0073] One or more fillers may be used in a total % w / w range of about 10 to 70, or about 17 to 45, or about 17 to 25, or about 35 to 40, or at about 19, or about 22, or about 23, or about 37.5, or about 38.5 % w / w, or about 37.75% w / w. A filler such as microcrystalline cellulose may be used in a % w / w range of about 7 to 40, or about 20 to 30, or about 8 to 15, or about 25 to 30, or at about 9, or about 12, or about 13, or about 29% w / w, or about 29.25% w / w, or about 30 % w / w. A filler such as lactose (e.g., lactose anhydrous) or mannitol, preferably lactose anhydrous, may be used in a % w / w range of about 5 to 25, or 5 to 20, or 7 to 18, or 5 to 10, or at about 8.5, or about 9.5, or about 10 % w / w. In some embodiments, the fillers are 37.75% w / w, including microcrystalline cellulose (e.g., at29.25% w / w) and lactose (e.g., at 8.5% w / w).

[0074] A binder such as hydroxypropyl cellulose may be used in a % w / w range of about 2 to 10, or about 3 to 7, or about 4 to 5, or at about 3%, or about 4%, or about 5% w / w.

[0075] An intragranular disintegrant such as croscarmellose sodium or crospovidone, preferably croscarmellose sodium, may be used in a % w / w range of about 1 to 6, or about 2 to 4, or at about 2%, or about 3% w / w.

[0076] A surfactant such as sodium lauryl sulfate maybe used in a % w / w range of about 0.3 to 2, or at about 1% w / w.

[0077] An extragranular disintegrant such as croscarmellose sodium or crospovidone, preferably croscarmellose sodium, may be used in a % w / w range of about 1 to 4, or about 1 to 3, or at about 2% w / w.

[0078] A lubricant such as magnesium stearate may be used in a % w / w range of about 0.3 to about 2, or about 0.5 to 1.5, or at about 0.75 or about 1% w / w. Optionally the lubricant can be in the extragranular portion.WSGR Docket No. 47535-760.601

[0079] A glidant such as colloidal silicon dioxide may be used in a % w / w range of about 0.1 to 1, or at about 0.5% w / w.

[0080] In some embodiments, the powder formulation comprises the following ingredients in the exemplary amounts or % w / w amounts listed in Table 4, scaled as appropriate to provide the desired dosage.Table 4.Abbreviations: % w / w=percent weight / weight.

[0081] In some embodiments, the powder formulation is prepared by crushing one or more tablets (number of tablets and Compound 1 content selected as needed to provide the desired dosage, such as any unit dosage amount described herein) with the compositions as described herein to provide a crushed tablet composition suitable for reconstitution. In some embodiments, the tablets are coated with a non -function al polyvinyl alcohol-based coating (e.g., Opadry II, such as Opadry II orange or beige, or Opadry II blue or purple). In some embodiments, the one or more tablets comprise about 25 to 800 mg, or about 50 to 500 mg, or about 50 to 200 mg, or about 200 to 500 mg, or about 100 mg, or about 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg, or about 200 mg, or about 300 mg, or about 400 mg, or about 500 mg, or about 600 mg of Compound 1 or a solvate thereof, or of a crystalline form of Compound 1 or a solvate thereof. In some embodiments, the one or more tablets comprise about 25 to 800 mg, or about 50 to 500 mg, or about 50 to 200 mg, or about 200 to 500 mg, or about 100 mg, or about 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg, or about200 mg, or about300 mg, or about400mg, or about500mg, or about 600 mg of Compound 1, Form 1. Additional embodiments of unit dosage amounts are described herein.WSGR Docket No. 47535-760.601Powders for Reconstitution

[0082] In one aspect, described herein is a powder formulation comprising Compound 1 or a solvate thereof, or a crystalline form of Compound 1 or a solvate thereof, or Compound 1 , Form 1, and a pharmaceutically acceptable excipient. In some embodiments, the powder formulation is suitable for reconstitution as an oral suspension.

[0083] In some embodiments, the powder formulation is a direct-blend powder formulation, where the active pharmaceutical ingredient is blended directly with one or more pharmaceutically acceptable ingredients. In some embodiments, the powder formulation is a granule powder formulation comprising granules (e.g., and intragranular portion) and an extragranular portion, wherein the granules comprise Compound 1 or a solvate thereof, or a crystalline form of Compound 1 or a solvate thereof, or Compound 1, Form 1 , and a pharmaceutically acceptable excipient, and the extragranular portion comprises a pharmaceutically acceptable excipient.

[0084] In some embodiments, the pharmaceutically acceptable excipient is selected from a thickening agent, a filler, a disintegrant, an anti-foaming agent, a sweetener, a buffering agent, a surfactant, and / or a glidant, and optionally a preservative. In some embodiments, the powder formulation comprises a thickening agent, a filler, a disintegrant, an anti-foaming agent, a sweetener, a buffering agent, a surfactant, and a glidant, and optionally a preservative.

[0085] In some embodiments, the powder formulation comprises a thickening agent, optionally wherein the thickening agent comprises xanthan gum (e.g., Xantural 75), cornstarch, modified starch, or erythritol, or a combination thereof. In some embodiments, the thickening agent comprises xanthan gum (e.g., Xantural 75).

[0086] In some embodiments, the powder formulation comprises a filler, optionally wherein the filler comprises maltodextrin, microcrystalline cellulose (e.g., Avicel CL-611), silicified microcrystalline cellulose, lactose (e.g., lactose anhydrous), sucrose, or mannitol, or a combination thereof. In some embodiments, the filler comprises maltodextrin, microcrystalline cellulose (e.g., Avicel CL-611), silicified microcrystalline cellulose, and sucrose. In some embodiments, the silicified microcrystalline cellulose comprises microcrystalline cellulose blended with colloidal silicon dioxide (e.g., 90%-99% w / w microcrystalline cellulose and 10%- 1% w / w colloidal silicon dioxide, such as 98% w / w microcrystalline cellulose and 2% w / w colloidal silicon dioxide). In some embodiments, the microcrystalline cellulose comprises a blend of microcrystalline cellulose (cellulose gel) and sodium carboxymethylcellulose (cellulose gum), such as a mixture of 82-89% microcrystalline cellulose and 11-18% sodium carboxymethylcellulose (e.g., Avicel CL-611).WSGR Docket No. 47535-760.601

[0087] In some embodiments, the powder formulation comprises a disintegrant, optionally wherein the disintegrant comprises croscarmellose sodium (e.g., Ac-Di-Sol) or crospovidone. In some embodiments, the disintegrant comprises croscarmellose sodium (e.g., Ac-Di-Sol).

[0088] In some embodiments, the powder formulation comprises an anti-foaming agent, optionally wherein the anti-foaming agent is simethicone.

[0089] In some embodiments, the powder formulation comprises a sweetener, optionally wherein the sweetener comprises sucrose, maltitol, dextrose, sorbitol, sucralose, aspartame, stevia, or a combination thereof. In some embodiments, the sweetener comprises sucrose, sucralose, or a combination thereof. Of note, while sucrose may be a sweetener at low concentrations, it functions as a filler at higher concentrations. In the formulations described herein, sucrose is characterized as a filler, but one of ordinary skill in the will recognize that sucrose also functions as a sweetener.

[0090] In some embodiments, the powder formulation comprises a buffering agent, optionally wherein the buffering agent comprises citric acid (e.g., anhydrous citric acid), sodium citrate, sodium phosphate, potassium phosphate, sodium bicarbonate, sodium acetate, or acetic acid, or a combination thereof. In some embodiments, the buffering agent comprises anhydrous citric acid and sodium citrate.

[0091] In some embodiments, the powder formulation comprises a surfactant, optionally wherein the surfactant comprises sodium lauryl sulfate (SLS) or a polysorbate. In some embodiments, the surfactant comprises polysorbate 80 (e.g., Tween 80).

[0092] In some embodiments, the powder formulation comprises a glidant, optionally wherein the glidant comprises colloidal silicon dioxide (e.g., Syloid 244 FP). In some embodiments, the colloidal silicon dioxide is porous and amorphous.

[0093] In some embodiments, the powder formulation comprises a preservative, optionally wherein the preservative comprises potassium sorbate, sodium benzoate, a paraben, benzalkonium chloride, or benzyl alcohol. In some embodiments, the preservative comprises potassium sorbate. In some embodiments, the powder formulation does not comprise a preservative.

[0094] In some embodiments, the powder formulation is a direct blend powder formulation comprising a filler, a sweetener, a buffering agent, a glidant, and a thickening agent, and optionally a surfactant and / or a preservative.

[0095] In some embodiments of the granule powder formulation, the granules are wet-granulated. In some embodiments, the granules are wet granulated with water or alcohol (e.g., ethanol or isopropanol). In some embodiments, the granules are wet granulated with water.WSGR Docket No. 47535-760.601

[0096] In some embodiments, the quantitative composition for the granule powder formulation comprises Compound 1 or a solvate thereof, such as a crystalline form of Compound 1 or a solvate thereof, or Compound 1 , Form 1 , and one or more the following excipients in the % w / w ranges listed in Tables 5A, 5B, and 5C.Table 5A.Abbreviations: % w / w=percent weight / weight.Table 5B.Abbreviations: % w / w=percent weight / weight.WSGR Docket No. 47535-760.601Table 5C.Abbreviations: % w / w=percent weight / weight.

[0097] In some embodiments, granule powder formulations comprise about 45 to about 55 % w / w, or about 50 % w / w of Compound 1. In such embodiments, the intragranular portion comprises: (a) about 25 to about 40 % w / w, or about 30 to about 35 % w / w, or about 33 % w / w filler; (b) about 2 to about 6 % w / w, or about 4 % w / w disintegrant; (c) about 0.1 to about 1 % w / w, or about 0.5 % w / w anti -foaming agent; or (d) about 0.1 to about 1 % w / w, or about 0.5 % w / w surfactant; or a combination of two or more of (a)-(d), or all of (a)-(d). In such embodiments, the extragranular portion comprises: (e) about 4 to about 8 % w / w, or about 5 to about 6% w / w filler; (f) about 0.05 to about 1 % w / w, or about 0.1 % w / w sweetener; (g) about 2 to about 8 % w / w, or about 4 to about 6 % w / w, or about 5% w / w buffering agent; (h) no disintegrant or about 0.1 to about 5 % w / w disintegrant; (i) about 0.5 to about 2 % w / w, or about 1 % w / w glidant; (j) about 0.1 to about 0.5 % w / w, or about 0.25 % w / w thickening agent; or (k) no preservative or about 0.1 to about 0.5 % w / w, or about 0.1 % w / w preservative; or a combination of two or more of (e)-(k); or all of (e)-(k).

[0098] In some embodiments, granule powder formulations comprise about 15 to about 30 % w / w of Compound 1. In some embodiments, the intragranular portion comprises: (a) about 25 to about 40 % w / w, or about 30 to about 35 % w / w, or about 30% w / w, or about 33 % w / w filler; (b) about 2 to about 6 % w / w, or about 2 % w / w, or about 4 % w / w disintegrant; (c) no anti-foaming agent or about 0.1 to about 1 % w / w, or about 0.5 % w / w anti -foaming agent; or (d) about 0.1 to about 1 % w / w, or about 0.5 % w / w surfactant; or a combination of two or more of (a)-(d), or all of (a)-(d). In such embodiments, the extragranular portion comprises: (e) about 30 to about 45 % w / w, or about 35 to about 40 % w / w, or about 35 to about 36 % w / w, or about 39 to about 40% w / w filler; (f) about 0.05 to about 1 %w / w, oraboutO.l % w / w sweetener; (g)WSGR Docket No. 47535-760.601about 2 to about 8 % w / w, or about 4 to about 6 % w / w, or about 5% w / w buffering agent; (h) no disintegrant or about 0.1 to about 5 % w / w disintegrant; (i) about 0.5 to about 2 % w / w, or about 1 % w / w glidant; (j) about 0.1 to about 0.5 % w / w, or about 0.25 % w / w thickening agent; or (k) no preservative or about 0.1 to about 0.5 % w / w, or about 0.1 % w / w preservative; or a combination of two or more of (e)-(k); or all of (e)-(k).

[0099] In other granule powder formulations comprising about 15 to about 30 % w / w of Compound 1, the intragranular portion comprises: (a) about 55 to about 70 % w / w, or about 60 to about 65 % w / w, or about 62 to about 63% w / w, or about 62.3% w / w filler; (b) about 2 to about 6 % w / w, or about 4 % w / w disintegrant; (c) about 0.1 to about 1 % w / w, or about 0.5 % w / w anti-foaming agent; or (d) about 0.1 to about 1 % w / w, or about 0.5 % w / w surfactant; or a combination of two or more of (a)-(d), or all of (a)-(d). In such embodiments, the extragranular portion comprises: (e) about 0.05 to about 1 % w / w, or about 0.1 % w / w sweetener; (f) about 2 to about 8 % w / w, or about 5 to about 7 % w / w, or about 6% w / w, or about 6.3% buffering agent; (g) about 0.5 to about 2 % w / w, or about 1 % w / w glidant; (h) about 0.1 to about 0.5 % w / w, or about 0.25 % w / w thickening agent; or (i) no preservative or about 0.1 to about 0.5 % w / w, or about 0.1 % w / w preservative; or a combination of two or more of (e)-(i); or all of (e)-(i).

[0100] In some embodiments, the extragranular buffering agents comprise citric acid (e.g., anhydrous citric acid) and sodium citrate. In some embodiments, the ratio of citric acid (e.g., anhydrous citric acid) and sodium citrate is about 1:2 to about 1:2.5 w / w. In some embodiments, the powder formulation comprises extragranular anhydrous citric acid at a % w / w of about 1 %, or about 1.2%, or about 1.4%, or about 1.6%, or about 1.8%, or about 2%, or about 2.2%, or about 2.4%, or about 2.6%. In some embodiments, the powder formulation comprises extragranular anhydrous citric acid at a % w / w of about 2%. In some embodiments, the powder formulation comprises extragranular anhydrous citric acid at a %w / w or about 1.6%.

[0101] In some embodiments, the powder formulation comprises extragranular sodium citrate at a % w / w of about 3%, or about 3.2%, or about 3.4%, or about 3.6%, or about 3.8%, or about 4%, or about 4.2%, or about 4.4%, or about 4.6%. In some embodiments, the powder formulation comprises extragranular sodium citrate at a % w / w of about 3.4%. In some embodiments, the powder formulation comprises extragranular anhydrous citric acid at a % w / w or about 4.2%. In some embodiments, the powder formulation comprises extragranular anhydrous citric acid at a % w / w or about 4.4%.

[0102] In some embodiments, the powder formulation comprises the following ingredients in the proportions listed in Table 6.WSGR Docket No. 47535-760.601Table 6.

[0103] In some embodiments, the powder formulation is Formulation N in Table 6. In some embodiments, the powder formulation is Formulation O in Table 6. In some embodiments, the powder formulation is Formulation Pin Table 6. In some embodiments, the powder formulation is Formulation Q in Table 6. In some embodiments, the powder formulation is Formulation R in Table 6. In some embodiments, the powder formulation is Formulation S in Table 6.

[0104] In some embodiments, the powder formulation is reconstituted with water and a flavoring agent, optionally wherein the flavoring agent is a fruit flavoring agent, a mint flavoring agent, a candy flavoring agent, or a cinnamon flavoring agent, or combinations thereof. In some embodiments, wherein the flavoring agent is the fruit flavoring agent. In some embodiments, theWSGR Docket No. 47535-760.601fruit flavoring agent is a strawberry, cherry, orange, mango, banana, pineapple, raspberry, grape, lemon, or mixed berry flavoring agent, or a combination thereof, optionally wherein the fruit flavoring agent is a strawberry flavoring agent. In some embodiments, the flavoring agent is the mint flavoring agent. In some embodiments, the mint flavoring agent is a peppermint or spearmint flavoring agent, or a combination thereof. In some embodiments, the flavoring agent is the candy flavoring agent. In some embodiments, the candy flavoring agent is a vanilla, anise, bubble gum, chocolate, butterscotch, or caramel flavoring agent, or a combination thereof. In some embodiments, the flavoring agent is the cinnamon flavor. In some embodiments, the flavoring agent is a strawberry flavor. In some embodiments, the flavoring agent is a fruit flavor, wherein the fruit flavor is juicy.Reconstitution Methods and Dosing

[0105] Powder formulations as described herein may be reconstituted in a suspension carrier, such as a liquid carrier or a soft food carrier, and may be administered orally, e.g., by swallowing (drinking or eating), by enteral feeding tube, or by syringe administration. In some embodiments, powder formulations may be reconstituted, e.g., in water, optionally with an added short-acting preservative, and stored until administration.

[0106] For a liquid preparation, the appropriate amount of powder formulation (optionally from opening capsules or crushing tablets or from the powder formulations described herein) is selected to provide the target dosage. The powder formulation is mixed with a liquid carrier to provide about 5 to 75 mg / mL, or 10 to 75 mg / mL, or 10 to 30 mg / mL, or 40 to 60 mg / mL, or 10, 20, 25, 30, 40, or 50 mg / mL, or 20 mg / mL, or 50 mg / mL, or about 8 to 20 mL of Compound 1 in a mixing container, and the mixture is stirred or swirled for at least 15 seconds or until homogeneous. The suspension is dosed to the patient, and the mixing container is rinsed with the same volume of carrier (e.g., water) and dosed to the patient twice. For example, for a 600 mg dose, for the open capsule formulation, three 200 mg capsules are opened to provide the powder formulation, which is mixed with 30 mL liquid carrier and dosed to the patient, followed by dosing with 2x30 mL rinses of the mixing container with water.

[0107] For a soft food preparation, the appropriate amount of powder formulation (optionally from opening capsules or crushing tablets) is selected to provide the target dosage, and the powder formulation is combined with about 1 teaspoon to 4 tablespoons of suspension carrier. The mixture is stirred vigorously until homogeneous, the mixture is dosed to the patient, and the mixing container is rinsed with 5-30 mL of water and dosed to the patient.

[0108] For an enteral feeding tube (e.g,. nasogastric tube or gastric tube) or syringe preparation, the appropriate amount of powder formulation (optionally from opening capsules orWSGR Docket No. 47535-760.601crushing tablets or from the powder formulations described herein) is selected to provide the target dosage, and the powder formulation is combined with suspension carrier (water or 0.9% saline) in a mixing container. The mixture is stirred or swirled for at least 15 seconds or until homogeneous. For the enteral feeding tube delivery, the tube is pre-wet with 5-10 mL of suspension carrier and the mixture is dosed to the patient using the feeding tube. For the syringe delivery, the mixture is dosed directly to the patient. In both cases, the mixing container is rinsed twice with 5-20 mL of suspension carrier and the rinse volumes are dosed to the patient.Methods

[0109] In some embodiments, described herein is a method of treating a disease or condition in a subject, comprising administering to the subject an oral suspension of Compound 1 or a solvate thereof described herein. In some embodiments, the oral suspension comprises a therapeutically effective amount of Compound 1 described herein. In some embodiments, the disease or condition is a menin-mediated disease, a hematologic malignancy, a solid tumor cancer, or diabetes. In some embodiments, the hematologic malignancy is leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or my elodysplastic / myeloproliferative neoplasm. In some embodiments, the leukemia is AML or ALL. In some embodiments, the AML is menin-dependent AML, KMT2A -rearranged AML, or NPM1 -mutant AML. In some embodiments, the ALL is KMT2A -rearranged ALL. In some embodiments, the solid tumor cancer is prostate cancer, breast cancer, liver cancer, or brain tumor. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.

[0110] In some embodiments, the method of treating comprises administering to the subject an oral suspension comprising Compound 1 or a solvate thereof, or a crystalline form of Compound 1 or a solvate thereof. In some embodiments, the methods comprise administering the oral suspension one or more times per day, such as once per day or twice per day. In some embodiments, the methods comprise administering the oral suspension comprising Compound 1 ora solvate thereof in an amount of 50 to 1200 mg, or 50 mg, 100 mg, 200 mg, 300 mg, 400 mg 500 mg, 600 mg, 700 mg, or 800 mg. In some embodiments, the methods comprise administering Compound 1 in an amount of 600 mg, once per day. In some embodiments, the oral suspension is prepared with a powder formulation that is an open capsule or crushed tablet formulation (e.g., from three 200 mgtablets or capsules, or two 300 mg tablets or capsules). In some embodiments, the oral suspension that is used is from reconstitution of a powderWSGR Docket No. 47535-760.601formulation as described herein (e.g., a direct blend powder formulation or a granule powder formulation). In some embodiments, the therapeutically effective amount is 400 mg, once per day, and can be administered, for example, using a powder formulation prepared from two 200 mg tablets or capsules, or one 400 mg tablet or capsule, or the appropriate amount of a direct blend or granule powder formulation.EXAMPLESI. Characterization of PolymorphsExample 1: X-ray Powder Diffraction (XRPD)

[0111] X-ray powder diffraction studies were performed using a Bruker D8 Advance with the following instrument parameters: X-Ray wavelength: Cu: K-Alpha (1 = 1.54179); X-Ray tube setting: Voltage: 40 kV; Current40 mA Scan scope: 4° (29) to 40° (29); Sample rotation speed: 15 rpm; Scanning rate: 10 deg / min.

[0112] XRPD analysis of Form 1 of Compound 1 (Figure 1) showed Form 1 to be crystalline with characteristic peaks at4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta.

[0113] XRPD analysis of Form 2 of Compound 1 showed Form 2 to be crystalline with characteristic peaks at 3.8° 2-Theta, 5.6° 2-Theta, 6.4° 2-Theta, 7.1° 2-Theta, 8.8° 2-Theta, 9.9° 2-Theta, 11.9° 2-Theta, and 14.8° 2-Theta.

[0114] XRPD analysis of Form 3 of Compound 1 showed Form 3 to be crystalline with characteristic peaks at 7.9° 2-Theta, 9.5°2-Theta, 11.0° 2-Theta, 15.7° 2-Theta, 16.5° 2-Theta, 18.0° 2-Theta, 19.0° 2-Theta, and 21.9° 2-Theta.

[0115] XRPD analysis of Form 4 of Compound 1 showed Form 4 to be crystalline with characteristic peaks at 8.1° 2-Theta, 9.4° 2-Theta, 10.8° 2-Theta, 13.5° 2-Theta, 15.7° 2-Theta, 16.3° 2-Theta, 17.5° 2-Theta, 18.3° 2-Theta, 18.7° 2-Theta, 20.1° 2-Theta, 21.6° 2-Theta, and 21.8° 2-Theta, 25.2° 2-Theta, and 25.7° 2-Theta.

[0116] XRPD analysis of Form 5 of Compound 1 showed Form 5 to be crystalline with characteristic peaks at 7.9° 2-Theta, 8.5° 2-Theta, 9.6° 2-Theta, 11.1° 2-Theta, 15.8° 2-Theta, 16.9° 2-Theta, 18.4° 2-Theta, 19.1° 2-Theta, 22.1° 2-Theta, and 25.5° 2-Theta, and 27.4° 2-Theta.

[0117] The XRPD traces for Compound 1, Forms 2, 3, 4, and 5, are reported in PCT. Appl. Publ. No. W02025 / 019497, which is incorporated herein by reference in its entirety.WSGR Docket No. 47535-760.601Example 2: Differential Scanning Calorimetry (DSC)

[0118] DSC studies were performed using a TA Discovery Q2000 or DSC250. The sample was weighed in crimped aluminum pan and the accurate amount was recorded. The sample was heated from room temperature or 30 °C to 250 °C or 300 °C at a heating rate of 10 °C / min with nitrogen purge.

[0119] DSC analysis of Form 1 of Compound 1 (Figure 2) showed an endotherm with onset at about 136 °C. DSC analysis of Form 1 of Compound 1 (Figure 2) showed an endotherm with a peak at about 149 °C.

[0120] DSC analysis of Form 3 of Compound 1 showed an endotherm with onset at about 117 °C and / or a peak at about 135 °C.

[0121] DSC analysis of Form 4 of Compound 1 showed an endotherm having an onset at about 45 °C and a peak at about 75 °C, and an endotherm having an onset at about 127 °C and a peak at about 138 °C.

[0122] DSC analysis of Form 5 of Compound 1 showed a melting endotherm with onset at about 122 °C and a peak at about 132 °C.

[0123] The DSC analyses for Compound 1, Forms 3, 4, and 5, are reported in PCT. Appl. Publ. No. W02025 / 019497, which is incorporated herein by reference in its entirety.Example 3: Thermogravimetric Analysis / Dynamic Vapor Sorption

[0124] Thermogravimetric analysis of solid was performed using TA Q5000IR. The sample was placed in an open platinum pan, the amount was weighed automatically. The sample was heated from 30 °C to 300 °C at a heating rate of 10 °C / min.

[0125] TGA of Form 1 of Compound 1 (Figure 3) showed about 0.6% weight loss over the range of about 29 °C to about 150°C.

[0126] TGA of Form 3 of Compound 1 showed about 1.33% weight loss over the range of about 29 °C to about 150 °C.

[0127] Dynamic vapor sorption testing was performed at 25 °C, with 10-15 mg of sample, under N2 at a flow rate of 200 mL / min, and drying at 0% relative humidity for 120 min.

[0128] DVS of Form 5 of Compound 1 was obtained. Compound 1, Form 5, contained less than 0.1%, or about 0.05%, residual EtOH, and KF analysis showed residual water content of about 0.5%.

[0129] The TGA and DVS data for Compound 1, Forms 3 and 5, are reported in PCT. Appl. Publ. No. W02025 / 019497, which is incorporated herein by reference in its entirety.WSGR Docket No. 47535-760.601II. Polymorph SynthesisExample 4: Preparations of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l-(2-(4-(methylsulfonyl)piperazin-l-yl)propyl)-lH-indole-2-carbonitrile (Compound 1), Form 1

[0130] Crystallization processes for producing Compound 1, Form 1, generally produced material with needle-like morphology, which resulted in poor bulk properties that impacted preparation of pharmaceutical compositions (e.g., flow, mobility in processing bulk material). Several approaches were investigated to improve the bulk properties, including modification of a MEK / IPA crystallization process, evaluation of alternative solvent systems, pH swing experiments, and spherical agglomeration analysis. Initial experiments to improve the bulk properties by adjusting the conditions of the MEK / IPA crystallization process did not significantly improve the properties. Solvent screening failed to deliver Form 1 material with bulk properties suitable for large-scale preparation, and pH swing experiments did not provide crystalline solid. Spherical agglomerations were prepared in a water / MEK system, but produced material with mixed properties (agglomeration and needle-like), included high levels of residual solvents, and poor flow properties, and the bulk properties worsened after de -lumping by sieve. Wet milling during MEK / IPA crystallization was investigated at various temperatures and conditions. After cooling to about 10 °C in MEK / IPA, the mobility of the suspension was low and precluded wet milling, necessitating implementation of this procedure at elevated temperature and with higher amounts of IPA. Wet milling at 40 °C followed by cooling to 5 °C produced a poor mobility suspension and ultimately material with needle-like morphology, perhaps due to low proportions of solid available at 40 °C for wet milling. Wet milling after warming to 40 °C and holding for 21 h, followed by cooling to 5 °C, provided a suspension with improved mobility. In additional experiments, two phases of wet milling were performed, one at 40 °C and a second at 25 °C. Thermal cycling did not improve bulk properties of the solid product.

[0131] Preparation A: Amorphous Compound 1 (prepared as described in U.S. Patent No.10,781,218, which is herein incorporated by reference in its entirety) was dissolved in 1:1 MEK / IPA v / v (4.5 mL / g) at -50-65 °C under N2. The solution was cooled to 33-37 °C. Seed crystals were added (0.8-1.2 wt% relative to Compound 1) and the mixture was stirred for 4-6 h at 33-37 °C. The mixture was cooled to 23-27 °C over 3-4 hours and stirred for 16-24 hours. Isopropanol (8.6 -9.1 mL / g Compound 1) was added at 23-27 °C over 9-11 hours and then the mixture was stirred for 5-6 hours. The mixture was cooled to 3-8 °C over 4-6 hours and stirred for at least 24 hours. The resulting solid precipitate was collected at 5 °C. The filter cake was rinsed with IPA (1.8-2.1 mL / g Compound 1) at 3 -8 °C and dried under vacuum at 45-55 °C forWSGR Docket No. 47535-760.60124-32 hours. XRPD analysis confirmed the isolated material as crystalline Compound 1, Form 1. Purity of 99.5% by HPLC and total residual solvents was about 0.4%wt by 'H NMR. Recrystallization of Compound 1, Form 1, in MEK / IPA (6v / 12v) by dissolving in MEK and adding IPA in portions at 25 °C, stirring the suspension after addition of each IPA portion, cooling to 5 °C, and stirring at 5 °C for 20 h produced a wet cake that was a mixture of two crystalline forms (Form 2 and Form 5) that were not Form 1. Under other recrystallization conditions, the resulting crystalline material has a low bulk density, small particle size, and needle-like morphology, leading to poor flowability and processability in preparing formulations. It was discovered that recrystallization from MEK / IPA at elevated temperatures produced Form 1. In this procedure, Compound 1 is dissolved in 2.5 v MEK, warmed to 40 °C, and treated with 17.5v IPA in portions. Following crystallization, the material is filtered at 25 °C to provide Form 1; however, upon standing, the material converted to Form 5. When performed at 50 °C, the procedure produced Form 1 material (99.5% purity) but material still was characterized by needle-like morphology. Extensive evaluation of other solvent systems, reversing addition of the solvents, other anti -solvents, and pH swing conditions did not provide material with improved morphology or suitable bulk properties. Including wet milling into the MEK / IPA crystallization process increased the bulk density from approximately less than 0.1 g / cm3, such as 0.07 or 0.08 g / cm3, to at least 0.1 g / cm3, or from about 0.1 to about 0.2 g / cm3, or from about 0.1 to about 0.15 g / cm3, or about 0.11, 0.12, 0.13, 0.14, or 0.15 g / cm3, or about 0.16, 0.17, 0.18, 0.19, or 0.20 g / cm3. Wet milling also improved the mobility of the suspension in the reaction vessel, which simplified filtration during manufacturing. In this process, Compound 1 is diluted in MEK / IPA and heated to 40 °C for 21 h, without temperature cycling, producing Form 1 material with improved bulk properties (bulk density of0.12g / mL). Use of micronized seed crystals also helped to improve the particle size distribution (reducing from D9029.7 um to 4.1 pm), which led to an improvement in bulk density (from 0.08 to 0.17 g / mL) and Hausner ratio (from 2.0 to 1.8). In some aspects, the crystalline Compound 1, Form 1, had a particle size distribution (as measured by light diffraction measurement per USP <429>) of: Di0, 1.5 to 4.5 pm, or about 2.0 to about 4.0 pm, or about 3.8 to about 3.9 pm, or about 2.9 to about 3.7 pm; D50, 5 to 11 pm, or about 5 to about 8 pm, or about 5.8 to about 7.7 pm, or about or about 9.5 to about 10.5 pm; orD90, 13 to 50 pm, or about33 to about 45 pm, or about 13 to about 26 pm, or about 13 to about 18 pm. .

[0132] Preparation B: Amorphous Compound 1 (1.8 g) was stirred in 30 mL toluene to form a clear solution, which was seeded with 6 mg of Compound 1 , Form 1. The resulting mixture was stirred for 1 day to obtain a turbid suspension. The resulting solid was collected by filtration,WSGR Docket No. 47535-760.601washed with IPA (50 mL), and vacuum-dried at30°C overnight to provide Compound 1, Form 1 (1.56 g). Purity was confirmed byJH NMR, HPLC, and XRPD.

[0133] Preparation C: Amorphous Compound 1 was diluted with MEK / IPA (2vol / 5vol ratio; 5.5vol) and the resulting mixture was heated to 65-75 °C and stirred for 0.5 to 3 h until all solids dissolved and a clear solution was obtained. The solution was polish -filtered into a pre-heated 65 to 75 °C vessel and was stirred for 0.5 to 3 h, then was cooled to 55 to 65 °C over 0.5 to 1 h, and was treated with a slurry of seed crystals (0.004-0.006 wt%) in IPA (0.01-0.06vol). The resulting mixture was stirred at 55 to 65 °C for 1 to 2 h, then cooled to 40 to 50 °C over 1 to 2 h, and stirred for 12 to 20 h. The mixture was heated to 50 to 60 °C over 1 to 2 h and stirred for 1 to 16 h. The resulting slurry was wet milled at 50 to 60 °C. Filtered IPA (7.2-8.2vol) was added at 50 to 60 °C over 8 to 12 h, and the resulting mixture was cooled to 0 to 10 °C over 4 to 6 h, then stirred at 0 to 10 °C for 16 to 24 h. The suspension was filtered at 0 to 10 °C and the filter cake was washed twice with cold IPA (2vol). The wet cake was dried under vacuum at 45 to 55 °C and the dry product was optionally sieved. Yield, 90%. Form 1 was confirmed by XRPD analysis.III. Pharmaceutical CompositionsExample 5: Composition and Preparation of Capsule Composition

[0134] Compound 1 drug substance may have a low bulk density, small particle size, and needle-like morphology, all leading to poor flowability. Dry granulation using roller compaction was improved the powder flow and bulk density characteristics to enable capsule -filling. In addition, while glidants such as talc and colloidal silicon dioxide were not effective in improving powder flow and bulk density characteristics, mannitol and microcrystalline cellulose fillers improved the blend flow in the roller compactor. Formulations exhibited good stability and excipient compatibility, and rapid dissolution suitable for an immediate release drug product.

[0135] Exemplary capsule formulations include the following amounts of Compound 1 and excipients shown in Table 7.Table 7.WSGR Docket No. 47535-760.601

[0136] Method A: Compound 1, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate are blended. Mannitol is added followed by magnesium stearate. The resulting lubricated blend is fed into a roller compactor for dry granulation. The generated ribbons are milled using a screen to create granules. For the 25.0 mg strength capsules, the % w / w amounts shownforthe excipients in the 50.0 mgcolumn are used to make granules, andthe resulting granules are mixed with mannitol to arrive at the % w / w amounts shown in the 25.0 mg column. Resulting granules for each strength are loaded into capsule shells.

[0137] Method B: Compound 1 is mixed with a mixture of microcrystalline cellulose, mannitol, croscarmellose sodium, and sodium lauryl sulfate, and the resulting blend is milled and then blended with 50% of the magnesium stearate. The resulting lubricated blend is fed into a roller compactor for dry granulation. The generated ribbons are milled to generate granules. The granules are mixed with the remaining 50% of magnesium stearate and the resulting mixture is encapsulated.

[0138] Capsule formulations may comprise Compound 1 as Form 1 or an amorphous form. Compound 1 may be used in an amount of about 15 to 800 mg. Mannitol may be used in a % w / w range of about 15 to 75, orabout25 to 35, or about25 to 30, or about 28 to 32, or about 65 to 70, or about 29% w / w or about 68% w / w. Microcrystalline cellulose may be used in a% w / w range of about 10 to 35, or about 10 to 15, or about 25 to 35, or about 25 to 30, or about 28 to 32, or about 13% or about 29%. Croscarmellose sodium may be usedin a% w / w range of about 1 to 10, orabout3 to 10, or about 1 to 8, or about4 to 8, or about 3% w / w, or about 6% w / w. Sodium lauryl sulfate may be used in a % w / w range of about 0.1 to 1.0, or about 0.2 to 0.8, or about 0.4 to 0.6, or about 0.2, or about 0.5. Magnesium stearate may be used in a % w / w range of about 0.1 to 1.0, or about 0.2 to 0.8, or about 0.4 to 0.6, or about 0.2%, or about 0.5.Example 6: Compositions and Preparation of Tablet Compositions

[0139] Excipient compatibility studies for tablet formulations indicated an impact to Compound 1 stability with certain excipients, such as mannitol, povidone, hydroxypropyl methylcellulose, and Opadry HPMC, for which use could require special precautions, particularly in tablet settings. In particular, these studies indicated less risk of instability in the presence of lactose as a diluent compared to mannitol.

[0140] Components of exemplary tablet compositions are provided in Table 8 (A) and Table 9 (B).WSGR Docket No. 47535-760.601Table 8. Composition (A).Abbreviations: % w / w=percent weight / weight.

[0141] Intragranular components, including Compound 1 (such as Compound 1, Form 1) were screened and then mixed for 1 min to provide a dry blend in a PMA-1 high shear granulator. Water (400 g for 1 kg batch) was sprayed at a rate of 100 g / min for 4 min at an impeller speed of 350 rpm and a chopper speed of 2200 rpm. Optionally, an additional portion of water (50 g) was sprayed for 30 sec under the same conditions. Alternatively, the hydroxypropylcellulose was dissolved in water and sprayed into the blend during granule formation. The resulting wet granules were screened through a Quadro Comil 197S equipped with a 250Q screen. The resulting granules were dried in an S-l fluid bed dryer and then dry milled by screening through a 062R screen. The dried, milled granules were blended with colloidal silicon dioxide and croscarmellose sodium and the resulting mixture was blended with magnesium stearate. The resulting blend was compressed on a Korsch XM-12 equipped with D-tooling to a target tablet weight of 800 mg (for 400 mg Compound 1). The resulting tablets were coated. For the final blends from the compositions in Table 6, bulk density was 0.48-0.52 g / mL, tapped density was 0.6-0.65 g / mL, and the Hausner Ratio was 1.25-1.28, with passable flow. Dissolution testing showed 82% dissolution at 10 min, 93-95% at 20 min, 97% at 30 min, and 99% at 60 min.WSGR Docket No. 47535-760.601Table 9. Composition (B).Abbreviations: % w / w=percent weight / weight.

[0142] Intragranular components, including Compound 1 (such as Compound 1, Form 1), were screened and then mixed to form a pre-blend, which was wet granulated to form granules, which were screened (#8 mesh), dried, and screened (#30 mesh) to form dry granules. The dry granules were blended with the extragranular ingredients and compressed into 200 mg and 500 mg tablets, which were coated. Target hardness range for tablets was 10 to 25 kp (e.g., 12kp for 200 mg tablets and 20 kp for 500 mg tablets).

[0143] Additional exemplary tablet compositions (C), (D), and (E) are provided in Table 10.Table 10.

[0144] Intragranular ingredients were mixed to form a pre-blend, which was wet-granulated with 25-30% water to form wet granules. The wet granules were screened through #4 mesh,WSGR Docket No. 47535-760.601dried, screened through #30 mesh, mixed with extra-granular ingredients, and compressed into tablets in 200 mg and 500 mg strengths. Bulk density of the final blends ranged from 0.12 (E) to 0.18 (D) g / mL, tapped density rangedfrom 0.26 (E)to 0.34 (D) g / mL, Carr’s Index ranged from 46 (D) to 56% (E), and Hausner Ratio ranged from 1.85 (D) to 2.30 (E). Disintegration times for tablets pressed at 2500 N: (C), 14 sec; (D), 20 sec; (E) 32 sec. Disintegration times for tablets pressed at 6000 N: (C), 32 sec; (D), 31 sec; (E) 29 sec. Adjustments were made to increase bulk density by using higher bulk density ingredients, such as microcrystalline cellulose (e.g., 0.43 vs. 0.32 g / mL) and lactose (0.72 vs. 0.59 g / mL), removing microcrystalline cellulose from extragranular portion and adding to intragranular portion, increasing binder component, removing mannitol, and adding colloidal silicon dioxide to the extragranular portion.

[0145] Exemplary composition (F) is shown in Table 11.Table 11.

[0146] The intragranular components were blended and wet granulated using a Key High Shear Granulator at water addition levels ranging from 40 to 60%. Bulk density of wet granules by water addition was: 40%, 0.34 g / cc; 45%, 0.38 g / cc; 50%, 0.47 g / cc; 55%, 0.52 g / cc; 60%, 0.59 g / cc. Granules were screened through a #4 mesh screen, screened granules were dried, and dried granules were screened using a #20 mesh screen. The dried granules were mixed with extragranular components to form the final blend (for 50% water example, bulk density, 0.12 g / mL, tap density, 0.26 g / mL, Carr’s Index, 56.5, Hausner Ratio, 2.30) and the final blend compressed into 200 and 500 mg strength tablets at 3000 N and 7500 N force, respectively. Dissolution (0.01 NHCl / 0.5% Tween 80): 200 mg tablets (50% water preparation), 98% at 10 min and 100% at20 min; 500 mgtablets (50% water preparation), 98% at 10 min, 100% at 20 min; 500 mgtablets (60% water preparation), 93% at 10 min, 99% at 20 min, 100% at 30 min. Although 60% water preparation increased bulk density to 0.59 g / mL, the material had an overgranulated appearance. In some aspects, for 500 mgtablets, the disintegrant amount is reduced by 1 % w / w.WSGR Docket No. 47535-760.601

[0147] Exemplary composition (G) is shown in Table 12.Table 12.

[0148] Intragranular components were blended (bulk density 0.13 g / mL, tap density 0.33 g / mL, Hausner’s Ratio, 2.54), then wet granulated with 50% water, screened (#8 mesh), dried (bulk density 0.30 g / mL, tap density 0.41 g / mL, Hausner’s Ratio 1.37), screened (#30 mesh), blended with extragranular excipients (bulk density 0.33 g / mL, tap density 0.44 g / mL, Hausner’s Ratio 1.33; passable flow), and compressed into 200 and 500 mg tablet strengths (good compressibility), and then coated with Opadry II. Dissolution profile for 200 mg tablets: 10 min, 93%; 30 min, 97%, 90 min, 99.2%. Dissolution profile for 500 mg tablets: 10 min, 91%; 30 min, 94%; 90 min, 98%. To improve the flow of the blend, colloidal silicon dioxide was added as a glidant in the extragranular portion, as shown in the exemplary composition provided in Table 7.

[0149] Exemplary compositions (H), (I), and (J) with 50% Compound 1 loading are shown in Table 13.Table 13.WSGR Docket No. 47535-760.601

[0150] Intragranular components were blended, with addition of hydroxypropylcellulose as a dry material with water spray or with hydroxypropylcellulose dissolved in water for spraying. The blend was wet granulated, the wet granules screened through a Quadro Comil 197S with a 250Q screen, and the resulting granules dried. Dry granules were screened through 062R screen and blended with croscarmellose sodium and colloidal silicon dioxide, and the resulting mixture was then blended with magnesium stearate. Final blend data: bulk density, 0.43-0.45 g / mL; tap density, 0.56-0.57 g / mL; Compressibility Index, 21-23%; flow character, passable. The final blends were compressed into tablets at 200, 300, or 400 mg strengths and coated with Opadry II. Dissolution profiles for (A) (5% HPC; 1% magnesium stearate) were similar to (H) and (I) (4% HPC; 0.75 vs. 1.0 % magnesium stearate) and to (J) (4% HPC; 0.75% magnesium stearate), and (A) and (J) were similar (differing in amount of water used during granulation, 43% vs. 48). Dissolution for 200, 300, and 400 mg tablets: 10 min, 66-79%; 20 min, 85-93%; 30 min, 92-97%; 60 min, 95-99%.Example 7: Powder Formulations and Oral Suspensions

[0151] The components and composition of various exemplary powder formulations are described in Examples 5 and 6. From Example 5 and other capsule contents described herein, the capsule contents may be prepared as a powder formulation for direct use or encapsulated in the capsule shell for later opening to provide the powder formulation. From Example 6 and other final tablet blends described herein, the final blends prior to compression and coating constitute powder formulations suitable for reconstitution, or the final tablet compositions may be crushed (e.g., with the back of a spoon, a mortar and pestle, or similar) to provide the powder formulation for reconstitution.

[0152] Exemplary oral suspensions are prepared from powder formulations as describedin the “Reconstitution Methods and Dosing” section.

[0153] Suspension carrier studies were conducted with 200 mg and 800 mg Compound 1, Form 1, in various suspension carriers (water, 0.9% saline, electrolyte solution (Pedialyte), apple juice (100%), orange juice (100%), whole milk, Ora-Sweet (Perrigo), chocolate syrup, yogurt (5% milkfat / plain), applesauce (no sugar added)).

[0154] Liquid Carrier: Contents from a 200 mg capsule were emptied into a 30 mL polypropylene dosing cup. Vehicle (10 mL) was used to suspend the contents with gentle stirring or swirling for at least 15 seconds or until homogeneous, and the mixture was transferred. The dosing cup was rinsed with 10 mL of water with gentle stirring or swirling for at least 15 seconds or until homogeneous and the rinse was transferred. The rinsing was repeated with 10 mL of water. For the 800 mg study, four 200 mg capsules were emptied into aWSGR Docket No. 47535-760.601120 mL specimen container and the same steps were followed using vehicle (40 mL) and water rinses (2x40 mL).

[0155] Soft Food Carrier: Capsule contents from a 200 mg capsule were emptied into a 30 mL polypropylene dosing cup. Vehicle (15 g, ~ 1 tbsp) of vehicle was added to the cup and the mixture was stirred vigorously with a spoon or spatula until the mixture was homogeneous. The dispersion was transferred. Water (10 mL) was used to rinse the dosing cup by stirring or swirling for at least 15 seconds or until homogeneous and the rinse mixture was transferred. The same procedure was followed for 800 mg, using four 200 mg capsules, 60 g (~ 4 tbsp) of vehicle, and rinsing with 30 mL of water.

[0156] Dissolution, stability (at 1, 2, and 4 hours), suspension recovery, and nasogastric tube recovery studies were conducted on the resulting suspensions.

[0157] Suspension samples were diluted with 0.1% trifluoroacetic acid (TFA) in acetonitrile (ACN) (50 mL for 200 mg; 250 mL for 800 mg) and sonicated for 10 min to dissolve. The mixture was diluted with water (to 100 mL for 200 mg; to 500 mL for 800 mg). A sample of the resulting solution (3.0 mL for 200 mg; 4.0 mL for 800 mg) was diluted to 25 mL with 0.05% TFA in 1 :1 ACN / waterfor a final sample concentration of 0.23 to 0.26 mg / mL. Samples were centrifuged to achieve a clear supernatant and evaluated by HPLC.

[0158] Dissolution analysis was conducted under the USP Type 2 (Paddles) method.Dissolution studies showed complete and rapid dissolution in water, orange juice, milk, and applesauce. Dissolution in yogurt was complete, but was slower and more variable.

[0159] For suspension recovery studies, 10 mL of 0.05% TFA in 1:1 ACN / water was added to the suspension vessel after simulated dosing. The diluent and vessel were sonicated to ensure complete dissolution of any residual Compound 1. The samples were centrifuged to achieve a clear supernatant and analyzed by HPLC. Recovery testing for the suspension and rinsing steps as described herein indicated efficient transfer of Compound 1 in water, orange juice, whole milk, applesauce, and yogurt vehicles at both dose levels (92 to 104% recovery; 0.0 to 4.1% residual). Nasogastric tube recovery studies were performed. The gastric tube (10 Fr nasogastric tube for 200 mg; 14 Fr gastric tube for 800 mg) was pre-wet with water or saline prior to transfer of the Compound 1 suspension. Capsule contents were mixed with water or 0.9% saline (5 mL for 200 mg; 20 mL for 800 mg) in a dosing cup. The suspension was stirred for at least 15 seconds and administered directly into a volumetric flask (100 mL for 200 mg; 500 mL for 800 mg) through the tube. Two water or saline rinse steps were used to rinse the dosing cup. The collected material was analyzed by HPLC as described. Recovery was highly efficient from the tube administration (95 to 99% for water carrier; 98 to 101% for O.9% saline carrier).WSGR Docket No. 47535-760.601

[0160] Stability analyses showed no significant deterioration (0.0 to 0.07% of Compound 1 at 1, 2, or 4 h in any of the vehicles tested (comparable to capsule control samples).Example 8: Powders for Reconstitution

[0161] Three different powders for oral suspension formulations comprising Compound 1 were prepared by direct blending of Compound 1 with excipients, and the resulting blends were visually tested for wetting and homogeneity. Each blended formulation (2 g) was suspended in 20 mL water, added in 10 mL portions. The formulations are shown below in Table 14. Table 14

[0162] Drug loading for Formulations L and M was reduced after Formulation K displayed poor wetting characteristics. Formulations L and M had improved wetting compared to Formulation K; however, suspension homogeneity was poor based on visual assessment.

[0163] Wet granulation approaches for preparing powder formulations were investigated. Unexpectedly, wet granulation of Compound 1 / excipient mixtures provided granules with suitable consistency, flowability, wettability, and homogeneity. Five different granule powders formulations were prepared. Intragranular excipients were blended and water applied until the granulation endpoint was reached using a granulator, such as a high shear granulator. The blended and wetted intragranular components were dried in a convection oven and subsequently milled (mill screen 040G). The milled components were then blended with extragranular excipients. The prepared granule powder formulations are shown below in Table 15 and the manufacturing parameters are shown below in Table 16.WSGR Docket No. 47535-760.601Table 15Table 16WSGR Docket No. 47535-760.601

[0164] Formulation N exhibited a very sudden granulation endpoint and created an undesirable dough-like texture, prompting coprecipitated microcrystalline cellulose / sodium carboxymethylcellulose and croscarmellose sodium to be moved to the intragranular portion from the extragranular portion of the formulation. As a result, Formulations O, P, Q, and R reached the granulation endpoint, while Formulation O was sensitive to over granulation and produced inconsistently sized granules. Addition of silicified microcrystalline cellulose to the intragranular portion of the formulation improved granulation characteristics, end point predictability, homogeneity of the final granular size, suspension wettability, and suspension uniformity for Formulations P, Q, and R.

[0165] Stability analyses were conducted with Formulation R and Formulation P at 25 °C / 60% relative humidity (RH) and 40 °C / 75% RH in open and closed containers for up to six months. Visual analysis did not detect any significant deterioration for either formulation when stored in a closed container, or at 25 °C / 60% RH for up to six months, and analytical analysis did not detect any active ingredient impurities under these conditions.

[0166] Granular suspension stability was evaluated for Formulations P and R in a one-week, in-use stability study. Suspensions were prepared at 20 mg / mL and 50 mg / mL Compound 1 in deionized water and evaluated for syringeability using an 18-gauge gavage needle. All suspensions were syringeable after 7 days indicating no agglomeration of Compound 1 or the excipients.

[0167] A 3.5 kgbatch of powder formulation (Formulation S; see Table 17) was manufactured as described below.Table 17WSGR Docket No. 47535-760.601

[0168] Maltodextrin, silicified microcrystalline cellulose, coprecipitated microcrystalline cellulose / sodium carboxymethylcellulose, croscarmellose sodium, sucralose, anhydrous citric acid, sodium citrate, sucrose, colloidal silicon dioxide, xanthan gum, and potassium sorbate were screened through a # 20 mesh screen. Simethicone, polysorbate 80, and purified water were transferred into a pot and mixed using an air mixer until a uniform solution was produced. Maltodextrin, Compound 1, coprecipitated microcrystalline cellulose / sodium carboxymethylcellulose, croscarmellose sodium, and silicified microcrystalline cellulose were transferred to a high shear granulator and mixed for 1 min at an impeller speed of 272 rpm (setting I) and a chopper speed of 1800 rpm (Setting I) (note: all subsequent mixing was conducted under the same 272 / 1800 rpm impeller / chopper speed conditions). The mixture was sprayed at a spray rate of 80 g / min for approx. 4 min. Purified water (125.0 g) was sprayed at a spray rate of 80 g / min for approx. 2 min (twice). The wet mass was kneaded for 1 min. Sucrose was transferred to the granulator bowl and mixed with the wet granules for 1 min. The wet mass was kneaded for 1 min.

[0169] The wet granules were screened through a Quadro Comil 197S equipped with 250Q screen at a speed of 1000 ± 100 rpm. The wet milled granules were transferred into an S-2 fluid bed dryer. The wet milled granules were dried in the S-2 at an inlet air temperature of 60 ± 5 °C and appropriate fluidization until the residual water tested as not more than 0.5 % w / w. The dry granules were screened through a Quadro Comil 197S equipped with 039R screen at a speed of 1000 ± 100 rpm. The dried milled granules were blended with sucralose, anhydrous citric acid, sodium citrate, colloidal silicon dioxide, xanthan gum, and potassium sorbate for 10 min at 25 rpm.

[0170] Formulation S exhibited excellent flow quality (based on angle of repose) and fair flow character (based on calculation from bulk / tapped density). Blend uniformity was 95.1% with 0.9% RSD confirming Compound 1 is uniformly distributed in the formulation. Stability analyses (ICH standards) were conducted on the powder formulation at 25 °C / 60% RH and 40 °C / 75% for up to three months. Visual analysis did not detect any significant deterioration for up to 3 months under either condition, and analytical analysis identified all related substance impurities as <0.05% at three months.WSGR Docket No. 47535-760.601IV. Biological DataExample 9: Fluorescence polarization assay

[0171] Fluorescence polarization (FP) competition experiments were performed to determine the effectiveness with which Compound 1 inhibits the menin-MLL interaction, reported as an IC50value. A fluorescein -labeled peptide containing the high affinity menin binding motif found inMLL was produced according to Yokoyama et al. (Cell, 2005, 123(2): 207-218). Binding of the labeled peptide (1.7 kDa) to the much larger menin (~67 kDa) is accompanied by a significant change in the rotational correlation time of the fluorop hore, resulting in a substantial increase in the fluorescence polarization and fluorescence anisotropy (excitation at 500 nm, emission at 525 nm). The effectiveness with which Compound 1 inhibits the menin-MLL interaction was measured in an FP competition experiment, wherein a decrease in fluorescence anisotropy correlates with inhibition of the interaction and was used as a read-out for IC50determination: Compound 1, IC50 (half-maximal inhibitory concentration) < 50 nM.Example 10: Pharmacokinetic study of suspended powder formulations in beagle dogs

[0172] Six female beagle dogs were injected intramuscularly with a single dose of pentagastrin (0.006 mg / kg) prior to oral dosing of Compound 1 (400 mg) in Formulation S suspended in 8 mL of water or oral dosing of a capsule comprising Compound 1 (400 mg). Blood samples were taken 0, 1, 2, 4, 6, 8, and 12 h after administration of Compound 1 and blood concentrations of Compound 1 were analyzed at each time point. The mean pharmacokinetic parameters for each formulation of Compound 1 are shown in Table 18. As shown, Formulation S exhibited approximately 1.5x higher exposure than the capsule formulation based on the measured AUC0-12 values.Table 18WSGR Docket No. 47535-760.601V. Clinical Taste StudyExample 11: Randomized, open label assessment of taste profile of Compound 1 reconstituted powder formulation

[0173] The taste preferences of 12 healthy adults aged 32-54 for Formulation S dispersed in different flavor systems were evaluated to assess palatability for use in adult and pediatric patients who cannot swallow solid dosage forms.

[0174] Participants tasted 4 mL of Formulation S in various taste-masked suspension carriers in a “sip and spit” study. Three test products were used in this study: 50 mg / mL Formulation S (unflavored), 50 mg / mL Formulation S flavored with strawberry, and 50 mg / mL Formulation S flavored with juicy optify. Immediately (within 10 min) after expulsion of each formulation, subjects started to complete a taste / palatability questionnaire individually and privately. A minimum washout of 30 min between tasting each formulation included cleansing of the palate using unsalted crackers and potable water. The results from the taste study are shown in Table 19.Table 19Median (Min-Max) presented above. Scores rated: 1 - dislike extremely, 2 - dislike very much, 3 - dislike moderately, 4 - dislike slightly, 5 - neither like nor dislike, 6 - like slightly, 7 - like moderately, 8 - like very much and 9 - like extremely.

Claims

WSGR Docket No. 47535-760.601CLAIMSWe Claim:

1. A pharmaceutical composition comprising (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-l-yl)methyl)-l-(2-(4-(methylsulfonyl)piperazin-l-yl)propyl)-lH-indole-2-carbonitrile (Compound 1) or a solvate thereof, wherein the pharmaceutical composition is a powder formulation suitable for reconstitution as an oral suspension.

2. The pharmaceutical composition of claim 1, comprising a crystalline form of Compound 1 or a solvate thereof.

3. The pharmaceutical composition of claim 1 or claim 2, wherein the crystalline form of Compound 1 is Form 1 having at least one of the following properties:(a) an X-ray powder diffraction (XRPD) pattern substantially similar to the one set forth in Figure 1;(b) an XRPD pattern with at least three characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2- Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta;(c) a differential scanning calorimetry (DSC) thermogram substantially similar to the one set forth in Figure 2;(d) a DSC thermogram with an endotherm having an onset at about 136°C and / or a peak at about 149°C;(e) a thermogravimetric analysis (TGA) curve substantially similar to the one set forth in Figure 3; or(f) combinations thereof.

4. The pharmaceutical composition of claim 3, wherein the crystalline form has an XRPD pattern substantially similar to the one set forth in Figure 1.

5. The pharmaceutical composition of claim 3, wherein the crystalline form has an XRPD pattern with at least five characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta.

6. The pharmaceutical composition of claim 3, wherein the crystalline form has a DSC thermogram substantially similar to the one set forth in Figure 2.

7. The pharmaceutical composition of claim 3, wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 136 °C or a peak at about 149 °C.WSGR Docket No. 47535-760.6018. The pharmaceutical composition of claim 3, wherein the crystalline form has a TGA curve substantially similar to the one set forth in Figure 3.

9. The pharmaceutical composition of claim 3, wherein the crystalline form is characterized as having properties (a), (b), (c), (d), and (e).

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the powder formulation comprises:a) the capsule contents from one or more capsules, or a portion thereof, comprising Compound 1 or a solvate thereof; orb) a crushed tablet composition from one or more tablets, or a portion thereof, comprising Compound 1 or a solvate thereof.

11. A pharmaceutical composition comprising Compound 1 or a solvate thereof, wherein the pharmaceutical composition is an oral suspension, optionally wherein the oral suspension comprises a suspension carrier.

12. The pharmaceutical composition of claim 11, comprising a crystalline form of Compound 1 or a solvate thereof.

13. The pharmaceutical composition of claim 12, comprising the crystalline form as described in any one of claims 3 to 9.

14. The pharmaceutical composition of any one of claims 11 to 13, comprising the powder formulation of any one of claims 1 to 10.

15. The pharmaceutical composition of any one of claims 2 to 14, wherein the crystalline form has a bulk density of at least 0.1 g / cm3.

16. The pharmaceutical composition of claim 15, wherein the crystalline form has a bulk density from about 0.1 to about 0.2 g / cm3, or from about 0.1 to about 0.15 g / cm3.

17. The pharmaceutical composition of any one of claims 2 to 10 or 12 to 16, wherein the crystalline form has a particle size distribution of Di0, 1.5 to 4.5 pm, or about 2.0 to about 4.0 pm, or about 3.8 to about 3.9 pm, or about 2.9 to about 3.7 pm; D50, 5 to 11 pm, or about 5 to about 8 pm, or about 5.8 to about 7.7 pm, or about or about 9.5 to about 10.5 pm; or D90, 13 to 50 pm, or about 33 to about 45 pm, or about 13 to about 26 pm, or about 13 to about 18 pm. In some aspects, the particle size distribution D90equal to or below 50 pm.

18. The pharmaceutical composition of anyone of claims 1 to 17, comprising 15 to 800 mg of Compound 1 or a solvate thereof.

19. The pharmaceutical composition of any of the preceding claims, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

20. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition comprises content from a capsule solid dosage form, and wherein the pharmaceuticallyWSGR Docket No. 47535-760.601acceptable excipient is selected from a filler, a disintegrant, a surfactant, and a lubricant, and combinations thereof, optionally wherein the filler is mannitol and / or microcrystalline cellulose, optionally wherein the disintegrant is croscarmellose sodium, optionally wherein the surfactant is sodium lauryl sulfate, and optionally wherein the lubricant is magnesium stearate.

21. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition comprises a crushed tablet composition, wherein the pharmaceutically acceptable excipient is selected from a filler, a binder, a disintegrant, a surfactant, a glidant, and a lubricant, and combinations thereof, optionally wherein the filler is microcrystalline cellulose, lactose, or mannitol, or a combination thereof, optionally wherein the binder is hydroxypropylcellulose, optionally wherein the disintegrant is croscarmellose sodium or crospovidone, optionally wherein the surfactant is sodium lauryl sulfate, optionally wherein the glidant is colloidal silicon dioxide, and optionally wherein the lubricant is magnesium stearate.

22. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition is a granule powder formulation, comprising granules and an extragranular portion, and wherein the pharmaceutically acceptable excipient is selected from a thickening agent, a filler, a disintegrant, an anti-forming agent, a sweetener, a buffering agent, a surfactant, and a glidant, and optionally a preservative, and combinations thereof.

23. The pharmaceutical composition of claim 22, comprising an intragranular portion and an extragranular portion.

24. The pharmaceutical composition of claim 22 or claim 23, wherein the granules are wet granulated.

25. The pharmaceutical composition of any one of claims 22 to 24, wherein the granule powder formulation comprises about 45 to about 55 % w / w, or about 50 % w / w of Compound 1; the intragranular portion comprises: (a) about 25 to about 40 % w / w, or about 30 to about 35 % w / w, or about 33 % w / w filler; (b) about 2 to about 6 % w / w, or about 4 % w / w disintegrant; (c) about 0.1 to about 1 % w / w, or about 0.5 % w / w anti -foaming agent; or (d) about 0.1 to about 1 % w / w, or about 0.5 % w / w surfactant; or a combination of two or more of (a)-(d), or all of (a)-(d); and the extragranular portion comprises: (e) about 4 to about 8 % w / w, or about 5 to about 6% w / w filler; (f) about 0.05 to about 1 % w / w, or about 0.1 % w / w sweetener; (g) about 2 to about 8 % w / w, or about 4 to about 6 % w / w, or about 5% w / w buffering agent; (h) no disintegrant or about 0.1 to about 5 % w / w disintegrant; (i) about 0.5 to about 2 % w / w, or about 1 % w / w glidant; (j) about 0.1 to about 0.5 % w / w, or about 0.25 % w / w thickening agent; or (k) no preservative or about 0.1 to about 0.5 % w / w, or about 0.1 % w / w preservative; or a combination of two or more of (e)-(k); or all of (e)-(k).WSGR Docket No. 47535-760.60126. The pharmaceutical composition of any one of claims 22 to 24, wherein the granule powder formulation comprises about 15 to about 30 % w / w of Compound 1 ; the intragranular portion comprises: (a) about 25 to about 40 % w / w, or about 30 to about 35 % w / w, or about 30% w / w, or about 33 % w / w filler; (b) about 2 to about 6 % w / w, or about 2 % w / w, or about 4 % w / w disintegrant; (c) no anti -foaming agent or about 0.1 to about 1 % w / w, or about 0.5 % w / w anti-foaming agent; or (d) about 0.1 to about 1 % w / w, or about 0.5 % w / w surfactant; or a combination of two or more of (a)-(d), or all of (a)-(d); and the extragranular portion comprises: (e) ab out 30 to ab out 45 % w / w, or ab out 35 to ab out 40 % w / w, or ab out 35 to ab out 36 % w / w, or about 39 to about 40% w / w filler; (f) about 0.05 to about 1 % w / w, or about 0.1 % w / w sweetener; (g) about 2 to about 8 % w / w, or about 4 to about 6 % w / w, or about 5% w / w buffering agent; (h) no disintegrant or about 0.1 to about 5 % w / w disintegrant; (i) about 0.5 to about 2 % w / w, or about 1 % w / w glidant; (j) about 0.1 to about 0.5 % w / w, or about 0.25 % w / w thickening agent; or (k) no preservative or about 0.1 to about 0.5 % w / w, or about 0.1 % w / w preservative; or a combination of two or more of (e)-(k); or all of (e)-(k).

27. The pharmaceutical composition of any one of claims 22 to 24, wherein the granule powder formulation comprises about 15 to about 30 % w / w of Compound 1 ; the intragranular portion comprises: (a) about 55 to about 70 % w / w, or about 60 to about 65 % w / w, or about 62 to about 63% w / w, or about 62.3% w / w filler; (b) about 2 to about 6 % w / w, or about 4 % w / w disintegrant; (c) about 0.1 to about 1 % w / w, or about 0.5 % w / w anti-foaming agent; or (d) about 0.1 to about 1 % w / w, or about 0.5 % w / w surfactant; or a combination of two or more of (a)-(d), or all of (a)-(d); and the extragranular portion comprises: (e) about 0.05 to about 1 % w / w, or about 0.1 % w / w sweetener; (f) about 2 to about 8 % w / w, or about 5 to about 7 % w / w, or about 6% w / w, or about 6.3% buffering agent; (g) about 0.5 to about 2 % w / w, or about 1 % w / w glidant; (h) about 0.1 to about 0.5 % w / w, or about 0.25 % w / w thickening agent; or (i) no preservative or about 0.1 to about 0.5 % w / w, or about 0.1 % w / w preservative; or a combination of two or more of (e)-(i); or all of (e)-(i).

28. The pharmaceutical composition of any one of claims 22 to 27, wherein the thickening agent comprises xanthan gum (e.g., Xantural 75), cornstarch, modified starch, or erythritol, or a combination thereof, optionally wherein the thickening agent comprises xanthan gum (e.g., Xantural 75).

29. The pharmaceutical composition of any one of claims 22 to 28, wherein the filler comprises maltodextrin, microcrystalline cellulose (e.g., Avicel CL-611), silicified microcrystalline cellulose, lactose (e.g., lactose anhydrous), sucrose, or mannitol, or a combination thereof, optionally wherein the filler is maltodextrin, microcrystalline cellulose (e.g., Avicel CL-611), silicified microcrystalline cellulose, and sucrose.WSGR Docket No. 47535-760.60130. The pharmaceutical composition of any one of claims 22 to 29, wherein the disintegrant comprises croscarmellose sodium (e.g., Ac-Di-Sol) or crospovidone, optionally wherein the disintegrant comprises croscarmellose sodium (e.g., Ac-Di-Sol).

31. The pharmaceutical composition of any one of claims 22 to 30, wherein the anti -foaming agent is simethicone.

32. The pharmaceutical composition of any one of claims 22 to 31, wherein the sweetener comprises sucrose, maltitol, dextrose, sorbitol, sucralose, aspartame, stevia, or a combination thereof, optionally wherein the sweetener is sucralose.

33. The pharmaceutical composition of any one of claims 22 to 32, wherein the buffering agent comprises citric acid (e.g., anhydrous citric acid), sodium citrate, sodium phosphate, potassium phosphate, sodium bicarbonate, sodium acetate, or acetic acid, or a combination thereof, optionally wherein the buffering agent comprises anhydrous citric acid and sodium citrate.

34. The pharmaceutical composition of any one of claims 22 to 33, wherein the surfactant comprises sodium lauryl sulfate (SLS) or a polysorbate, optionally wherein the surfactant comprises polysorbate 80 (e.g., Tween 80).

35. The pharmaceutical composition of any one of claims 22 to 34, wherein the glidant comprises colloidal silicon dioxide (e.g., Syloid 244 FP).

36. The pharmaceutical composition of any one of claims 22 to 35, comprising a preservative, wherein the preservative comprises potassium sorbate, sodium benzoate, a paraben, benzalkonium chloride, or benzyl alcohol, optionally wherein the preservative comprises potassium sorbate.

37. The pharmaceutical composition of claim 1, comprising the composition as described in any one of Formulations A to S, or in any one of Tables 1 to 17, or in the Examples.

38. A pharmaceutical composition comprising the powder formulation of any one of claims 1 to 37 and a suspension carrier.

39. A method of treating a disease or condition in a subject comprising administering orally to the subject the pharmaceutical composition of any one of claims 1 to 38, wherein the disease or condition comprises a menin-mediated disease, a hematologic malignancy, a solid tumor cancer, or diabetes.

40. The method of claim 39, wherein the hematological malignancy is leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, menin -dependent AML, KMT2A -rearranged AML, or NPM1 -mutant AML.WSGR Docket No. 47535-760.60141. The method of claim 39 or claim 40, comprising:mixing the pharmaceutical composition of any one of claims 1 to 37 with a suspension carrier to form an oral suspension; andadministering the oral suspension to the subject.

42. The method of any one of claims 39 to 41 , comprising opening one or more capsule solid dosage forms or crushing one or more tablet solid dosage forms comprising Compound 1 or a solvate thereof, or a crystalline form of Compound 1 or a solvate thereof, or Compound 1, Form 1, to provide the powder formulation.

43. The method of any one of claims 39 to 42, wherein the administering orally is by mouth, by enteral feeding tube, or by syringe.

44. The pharmaceutical composition of claim 38 or the method of any one of claims 41 to 43, wherein the suspension carrier is a liquid vehicle or a soft food vehicle; optionally wherein the suspension carrier is a liquid vehicle; optionally wherein the liquid vehicle is selected from water, saline solution, electrolyte solution (e.g., Pedialyte), milk, coconut milk, soybean milk, buttermilk, fruit juice (e.g., orange, apple, cranberry, grapefruit, or pineapple juice), honey, or syrup (e.g., maple, chocolate, or flavoring syrup (such as Ora-sweet)), or is water, saline solution, milk, or fruit juice, oris water; optionally wherein the suspension carrier is a soft food vehicle; optionally wherein the soft food vehicle is pureed fruit (e.g., apples, bananas, strawberries), applesauce (e.g., no sugar addedapplesauce), jellies or jams (e.g., fruit jelly, fruit jam, fruit marmalade), yogurt, pudding (e.g., chocolate, rice), ice cream shake (e.g., vanilla or chocolate shake), pureed vegetables (e.g., carrots), or a nut or seed butter (e.g., peanut butter, sunflower seed butter, almond butter).

45. The method of claim 44, wherein the suspension carrier comprises a flavoring agent, optionally wherein the suspension carrier comprises water and a flavoring agent.

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